Quinoxaline derivatives and their uses

Abstract

The present disclosure relates to compounds of formula (I'), and pharma- ceutically acceptable salts and stereoisomers thereof. The disclosure also relates to methods of preparing these compounds, compositions containing these compounds, and methods of using these compounds, for example, in the treatment of cancer. JPEG2024512874000500.jpg2980

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 146,312, filed February 5, 2021, U.S. Provisional Patent Application No. 63 / 223,255, filed July 19, 2021, and U.S. Provisional Patent Application No. 63 / 242,260, filed September 9, 2021, each of which is incorporated by reference in its entirety. [Background technology]

[0002] Specific mutations in the human genes FGFR2 and FGFR3, which encode the FGFR2 and FGFR3 proteins, respectively, are associated with several different types of cancer. A variety of different inhibitors of FGFR2 and / or FGFR3 have been developed for the treatment of cancer, including FDA-approved drugs such as erdafitinib and pemigatinib. However, existing inhibitors exhibit various defects that limit their clinical effectiveness. First, some existing inhibitors target only FGFR2 and do not inhibit FGFR3, limiting their ability to treat certain types of cancer. Furthermore, some existing inhibitors also target FGFR1, resulting in dose-limiting toxicities such as hyperphosphatemia. Finally, after administration of some existing inhibitors, many patients develop additional mutations in FGFR2 and / or FGFR3, called gatekeeper mutations, resulting in resistance to the existing inhibitors. Therefore, there is a long-felt need in the art for new therapies that specifically target FGFR2 and FGFR3. The present disclosure provides compositions and methods for preventing or treating cancer in patients with overexpression and / or oncogenic mutations of FGFR2 and / or FGFR3, and FGFR2 and / or FGFR3. Summary of the Invention

[0003] In some aspects, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N; R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to one double bond and one single bond, C(R W2 ) and when connected to two single bonds, N(R W2 ) or O, or when connected to one double bond and one single bond, is N; R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, W 4 is C(R W4 ) or N, R W4 is H, halogen, cyano, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 5 is C(R W5 ) or N, R W5 is H, halogen, cyano, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 6 is connected to one double bond and one single bond, C(R W6 ) and when connected to two single bonds, N(RW6 ) or when connected to one double bond and one single bond, N; R W6 is H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or —S(═O)2—(C1-C6 alkyl); X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 3 is H, halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, and the above-mentioned -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a and optionally substituted with Each R 3a are independently halogen, cyano, oxo, -OH, NH2, -NH(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the NHC(=O)O(C1-C6 alkyl) is optionally substituted with one or more halogens; R 5 is H, halogen, cyano, or C1-C6 alkyl; R 6 is H, halogen, cyano, or C1-C6 alkyl; Y is absent, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl is selected from the group consisting of one or more halogen, oxo, cyano, —OH, NH2, —NH(C1-C6 alkyl)—OH, C1-C6 alkyl, C2-C6 alkenyl, —(C1-C6 alkyl)(C6-C 10 C1-C6 alkoxy optionally substituted with aryl, or C3-C 12 optionally substituted with cycloalkyl; Z is absent, H, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl or 5-10 membered heteroaryl, and the C3-C 12Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, ═NR Za , NH2, NHR Za , NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(=O)(=NR Za )-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl, a 3- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za and optionally substituted with Each R Za are independently H, oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C12 Cycloalkyl, or 3-12-membered heterocycloalkyl, and the above-mentioned NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0004] In some aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N; R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to one double bond and one single bond, C(RW2 ) and when connected to two single bonds, N(R W2 ) or when connected to one double bond and one single bond, N; R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2 is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is absent or is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is H, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R Z and optionally substituted with Each R Zare independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Za are independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0005] In some aspects, the present disclosure provides isotopic derivatives of the compounds described herein.

[0006] In some aspects, the disclosure provides methods of preparing the compounds described herein.

[0007] In some aspects, the present invention provides pharmaceutical compositions comprising one of the compounds described above and a pharmaceutically acceptable carrier or excipient.

[0008] In some aspects, the disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound described herein.

[0009] In some aspects, the disclosure provides a compound described herein for use in treating or preventing cancer in a subject.

[0010] In some aspects, the present disclosure is directed to the use of a compound described herein in the manufacture of a medicament for treating or preventing cancer in a subject.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between a chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0012] Features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0013] Compounds of the Disclosure

[0014] In some aspects, the present disclosure provides a compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N; R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to one double bond and one single bond, C(R W2 ) and when connected to two single bonds, N(R W2 ) or O, or when connected to one double bond and one single bond, is N; R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, W 4 is C(R W4 ) or N, R W4is H, halogen, cyano, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 5 is C(R W5 ) or N, R W5 is H, halogen, cyano, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 6 is connected to one double bond and one single bond, C(R W6 ) and when connected to two single bonds, N(R W6 ) or when connected to one double bond and one single bond, N; R W6 is H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or —S(═O)2—(C1-C6 alkyl); X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 3 is H, halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10Aryl or 5-10 membered heteroaryl, and the above-mentioned -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a and optionally substituted with Each R 3a are independently halogen, cyano, oxo, -OH, NH2, -NH(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the NHC(=O)O(C1-C6 alkyl) is optionally substituted with one or more halogens; R 5 is H, halogen, cyano, or C1-C6 alkyl; R 6 is H, halogen, cyano, or C1-C6 alkyl; Y is absent, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl is selected from the group consisting of one or more halogen, oxo, cyano, —OH, NH2, —NH(C1-C6 alkyl)—OH, C1-C6 alkyl, C2-C6 alkenyl, —(C1-C6 alkyl)(C6-C 10C1-C6 alkoxy optionally substituted with aryl, or C3-C 12 optionally substituted with cycloalkyl; Z is absent, H, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl or 5-10 membered heteroaryl, and the C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, ═NR Za , NH2, NHR Za , NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(=O)(=NR Za )-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12A cycloalkyl, a 3- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za and optionally substituted with Each R Za are independently H, oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 Cycloalkyl, or 3-12-membered heterocycloalkyl, and the above-mentioned NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, or 3- to 12-membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0015] In some aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N; R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to one double bond and one single bond, C(R W2 ) and when connected to two single bonds, N(R W2 ) or when connected to one double bond and one single bond, N; R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2 is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is absent or is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is H, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Za are independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zbare independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0016] In some aspects, the disclosure provides a compound of formula (I'), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N; R W1 is H, W 2 is connected to one double bond and one single bond, C(R W2 ) and when connected to two single bonds, N(R W2 ) or O, or when connected to one double bond and one single bond, is N; R W2 is H, W 3 is N, W 4 is C(R W4 ) and R W4 is H or a halogen, W 5 is C(R W5 ) and R W5 is H or a halogen, W 6 is connected to one double bond and one single bond, C(RW6 ) and when connected to two single bonds, N(R W6 ) or when connected to one double bond and one single bond, N; R W6 is H or C1-C6 alkyl, X 1 is N, X 2 is C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is C(R X3 ) and R X3 is H or C1-C6 alkyl, R 3 is H, halogen, cyano, NH2, NHC(=O)O(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or 5- to 10-membered heteroaryl, and the above-mentioned —NHC(═O)O(C1-C6 alkyl), —S(═O)2-(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), —C(═O)O(C1-C6 alkyl), C1-C6 alkyl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkenyl, or 5- to 10-membered heteroaryl may be selected from the group consisting of one or more R 3a and optionally substituted with Each R 3aare independently halogen, oxo, —NHC(═O)O(C1-C6 alkyl), —S(═O)2-(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), —C(═O)O(C1-C6 alkyl), C1-C6 alkyl, or C2-C6 alkenyl, wherein said NHC(═O)O(C1-C6 alkyl), —S(═O)2-(C1-C6 alkyl), —C(═O)(C1-C6 alkyl), —C(═O)O(C1-C6 alkyl), C1-C6 alkyl, or C2-C6 alkenyl is optionally substituted with one or more halogens; R 5 is H or C1-C6 alkyl, R 6 is H or a halogen, Y is absent, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl is selected from the group consisting of one or more halogen, oxo, cyano, —OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, —(C1-C6 alkyl)(C6-C 10 C1-C6 alkoxy optionally substituted with aryl, or C3-C 12 optionally substituted with cycloalkyl; Z does not exist, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl or 5-10 membered heteroaryl, and the C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, -OH, ═NR Za , NH2, NHR Za , NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(=O)(=NR Za)-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, and is selected from the group consisting of NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(C1-C6 alkyl), -S(=O)(=NR Za )-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl, a 3- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za and optionally substituted with Each R Za are independently H, oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyl, C3-C 12 Cycloalkyl, or 3-12 membered heterocycloalkyl, and the above-mentioned NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each RZb are independently oxo, halogen, or —OH.

[0017] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to two single bonds, C(R W1 ) or N(R W1 ) or when connected to one double bond and one single bond, is C or N, R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to two single bonds, C(R W2 ) or N(R W2 ) or when connected to one double bond and one single bond, is C or N, R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is absent or is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Zaare independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0018] In some aspects, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to two single bonds, C(R W1 ) or N(R W1 ) or when connected to one double bond and one single bond, is C or N, R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W2 is connected to two single bonds, C(R W2 ) or N(R W2 ) or when connected to one double bond and one single bond, is C or N, R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2 is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Z and optionally substituted with Each R Zare independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Za are independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0019] Variables n and W 1 , R W1 , W 2 , R W2 , W 3 , W 4 , R W4 , W 5 , R W5 , W 6 , and R W6 In some embodiments, each [ka] independently represent a single bond or a double bond.

[0020] In some embodiments, each [ka] independently represent a single bond. In some embodiments, each [ka] independently represent a double bond.

[0021] In some embodiments, n is 0. In some embodiments, n is 1.

[0022] In some embodiments, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N.

[0023] In some embodiments, W 1 is connected to one double bond and one single bond, C(R W1 )

[0024] In some embodiments, W 1 is connected to two single bonds, N(R W1)

[0025] In some embodiments, W 1 is N when connected to one double bond and one single bond.

[0026] In some embodiments, W 1 is C(R W1 ) or N(R W1 )

[0027] In some embodiments, W 1 is C(R W1 In some embodiments, W 1 is CH.

[0028] In some embodiments, W 1 is N(R W1 In some embodiments, W 1 is NH.

[0029] In some embodiments, W 1 is N(-S(=O)2-(C1-C6 alkyl)). In some embodiments, W 1 is N(-S(=O)2-CH3).

[0030] In some embodiments, W 1 is N.

[0031] In some embodiments, R W1 is H.

[0032] In some embodiments, R W1 is C1-C6 alkyl, or -S(=O)2-(C1-C6 alkyl).

[0033] In some embodiments, R W1 is C1-C6 alkyl.

[0034] In some embodiments, R W1 is -S(=O)2-(C1-C6 alkyl). In some embodiments, RW1 is -S(=O)2-CH3.

[0035] In some embodiments, W 2 is connected to one double bond and one single bond, C(R W2 ) and when connected to two single bonds, N(R W2 ) or when connected to one double bond and one single bond, N.

[0036] In some embodiments, W 2 is connected to one double bond and one single bond, C(R W2 )

[0037] In some embodiments, W 2 is connected to two single bonds, N(R W2 )

[0038] In some embodiments, W 2 is N when connected to one double bond and one single bond.

[0039] In some embodiments, W 2 is C(R W2 ) or N(R W2 )

[0040] In some embodiments, W 2 is C(R W2 In some embodiments, W 2 is CH.

[0041] In some embodiments, W 2 is N(R W2 In some embodiments, W 2 is NH.

[0042] In some embodiments, W 2 is N(-S(=O)2-(C1-C6 alkyl)). In some embodiments, W 2 is N(-S(=O)2-CH3).

[0043] In some embodiments, W 2 is N.

[0044] In some embodiments, W 2 is H.

[0045] In some embodiments, R W2 is C1-C6 alkyl, or -S(=O)2-(C1-C6 alkyl).

[0046] In some embodiments, R W2 is C1-C6 alkyl.

[0047] In some embodiments, R W2 is -S(=O)2-(C1-C6 alkyl). In some embodiments, R W2 is -S(=O)2-CH3.

[0048] In some embodiments, W 3 is C. In some embodiments, W 3 is N.

[0049] In some embodiments, W 4 is C(R W4 In some embodiments, W 4 is CH. In some embodiments, W 4 is C (halogen).

[0050] In some embodiments, W 4 is N.

[0051] In some embodiments, R W4 is H.

[0052] In some embodiments, R W4 is halogen, cyano, C1-C6 alkyl, or —S(═O)2—(C1-C6 alkyl).

[0053] In some embodiments, R W4is halogen or cyano.

[0054] In some embodiments, R W4 is a halogen. In some embodiments, R W4 is F, Cl, Br, or I. In some embodiments, R W4 is F. In some embodiments, R W4 is Cl. In some embodiments, R W4 is Br. In some embodiments, R W4 is I.

[0055] In some embodiments, R W4 is cyano.

[0056] In some embodiments, R W4 is C1-C6 alkyl.

[0057] In some embodiments, R W4 is -S(=O)2-(C1-C6 alkyl). In some embodiments, R W4 is -S(=O)2-CH3.

[0058] In some embodiments, W 5 is C(R W5 In some embodiments, W 5 is CH. In some embodiments, W 5 is C (halogen).

[0059] In some embodiments, W 5 is N.

[0060] In some embodiments, R W5 is H.

[0061] In some embodiments, R W5 is halogen, cyano, C1-C6 alkyl, or —S(═O)2—(C1-C6 alkyl).

[0062] In some embodiments, R W5is halogen or cyano.

[0063] In some embodiments, R W5 is a halogen. In some embodiments, R W5 is F, Cl, Br, or I. In some embodiments, R W5 is F. In some embodiments, R W5 is Cl. In some embodiments, R W5 is Br. In some embodiments, R W5 is I.

[0064] In some embodiments, R W5 is cyano.

[0065] In some embodiments, R W5 is C1-C6 alkyl.

[0066] In some embodiments, R W5 is -S(=O)2-(C1-C6 alkyl). In some embodiments, R W5 is -S(=O)2-CH3.

[0067] In some embodiments, W 6 is connected to one double bond and one single bond, C(R W6 ) and when connected to two single bonds, N(R W6 ) or when connected to one double bond and one single bond, N.

[0068] In some embodiments, W 6 is connected to one double bond and one single bond, C(R W6 )

[0069] In some embodiments, W 6 is connected to two single bonds, N(R W6 )

[0070] In some embodiments, W 6is N when connected to one double bond and one single bond.

[0071] In some embodiments, W 6 is C(R W6 ) or N(R W6 )

[0072] In some embodiments, W 6 is C(R W6 In some embodiments, W 6 is CH.

[0073] In some embodiments, W 6 is N(R W6 In some embodiments, W 6 is NH.

[0074] In some embodiments, W 6 is N(-S(=O)2-(C1-C6 alkyl)). In some embodiments, W 6 is N(-S(=O)2-CH3).

[0075] In some embodiments, W 6 is N.

[0076] In some embodiments, R W6 is H.

[0077] In some embodiments, R W6 is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or —S(═O)2—(C1-C6 alkyl).

[0078] In some embodiments, R W6 is halogen or cyano.

[0079] In some embodiments, R W6 is a halogen. In some embodiments, R W6 is F, Cl, Br, or I. In some embodiments, R W6is F. In some embodiments, R W6 is Cl. In some embodiments, R W6 is Br. In some embodiments, R W6 is I.

[0080] In some embodiments, R W6 is cyano.

[0081] In some embodiments, R W6 is C1-C6 alkyl.

[0082] In some embodiments, R W6 is C1-C6 alkoxy.

[0083] In some embodiments, R W6 is C1-C6 haloalkyl.

[0084] In some embodiments, R W6 is -S(=O)2-(C1-C6 alkyl). In some embodiments, R W1 is -S(=O)2-CH3.

[0085] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0086] Variable X1 , X 2 , R X2 , X 3 , and R X3 In some embodiments, X 1 is C. In some embodiments, X 1 is N.

[0087] In some embodiments, X 2 is N. In some embodiments, X 2 is O.

[0088] In some embodiments, X 2 is C(R X2 In some embodiments, X 2 is CH. In some embodiments, X 2 is C(C1-C6 alkyl). In some embodiments, X 2 is C(CH3).

[0089] In some embodiments, R X2 is H.

[0090] In some embodiments, R X2 is C1-C6 alkyl. In some embodiments, R X2 is CH3.

[0091] In some embodiments, X 3 is N. In some embodiments, X 3 is O.

[0092] In some embodiments, X 3 is C(R X3 In some embodiments, X 3 is CH. In some embodiments, X 3 is C(C1-C6 alkyl). In some embodiments, X 3 is C(CH3).

[0093] In some embodiments, R X3 is H.

[0094] In some embodiments, R X3 is C1-C6 alkyl. In some embodiments, R X3 is CH3.

[0095] In some embodiments, X 1 is N and X 2 is C(R X2 ) and X 3 is C(R X3 )

[0096] In some embodiments, X 1 is C and X 2 is C(R X2 ) and X 3 is O.

[0097] In some embodiments, [ka] teeth, [ka] is.

[0098] In some embodiments, [ka] teeth, [ka] is.

[0099] In some embodiments, [ka] teeth, [ka] is.

[0100] In some embodiments, [ka] teeth, [ka] is.

[0101] In some embodiments, [ka] teeth, [ka] is.

[0102] In some embodiments, [ka] teeth, [ka] is.

[0103] Variable R 1 , R 2 , R 3 , R 3a , R 4 , R 5 , and R 6 In some embodiments, R 1 is H.

[0104] In some embodiments, R 1 is halogen, cyano, or C1-C6 alkyl.

[0105] In some embodiments, R 1 is a halogen. In some embodiments, R 1 is F or Cl.

[0106] In some embodiments, R 1is F. In some embodiments, R 1 is Cl.

[0107] In some embodiments, R 1 is cyano.

[0108] In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is CH3.

[0109] In some embodiments, R 2 is H.

[0110] In some embodiments, R 2 is halogen, cyano, or C1-C6 alkyl.

[0111] In some embodiments, R 2 is a halogen. In some embodiments, R 2 is F or Cl.

[0112] In some embodiments, R 2 is F. In some embodiments, R 2 is Cl.

[0113] In some embodiments, R 2 is cyano.

[0114] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is CH3.

[0115] In some embodiments, R 3is H, halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, and the above-mentioned -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a is optionally substituted with

[0116] In some embodiments, R 3 is H, halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 It is aryl or 5- to 10-membered heteroaryl.

[0117] In some embodiments, R 3 is H.

[0118] In some embodiments, R 3 is halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, and the above-mentioned -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a is optionally substituted with

[0119] In some embodiments, R 3is halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 It is aryl or 5- to 10-membered heteroaryl.

[0120] In some embodiments, R 3 is halogen, cyano, NH, -NH(C-C alkyl), -NHC(=O)(C-C haloalkyl), -NHC(=O)O(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)H, -C(=O)(C-C alkyl), or -C(=O)O(C-C alkyl), and the -NH(C-C alkyl), -NHC(=O)(C-C haloalkyl), -NHC(=O)O(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)H, -C(=O)(C-C alkyl), or -C(=O)O(C-C alkyl) is selected from the group consisting of one or more R 3a is optionally substituted with

[0121] In some embodiments, R 3 is halogen, cyano, NH, —NH(C-C alkyl), —NHC(═O)(C-C haloalkyl), —NHC(═O)O(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)H, —C(═O)(C-C alkyl), or —C(═O)O(C-C alkyl).

[0122] In some embodiments, R 3is NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), or -C(=O)O(C1-C6 alkyl), and the -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), or -C(=O)O(C1-C6 alkyl) is selected from the group consisting of one or more R 3a is optionally substituted with

[0123] In some embodiments, R 3 is NH, —NH(C-C alkyl), —NHC(═O)(C-C haloalkyl), —NHC(═O)O(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)H, —C(═O)(C-C alkyl), or —C(═O)O(C-C alkyl).

[0124] In some embodiments, R 3 is NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), or N(C1-C6 alkyl)2, and the -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), or N(C1-C6 alkyl)2 is selected from the group consisting of one or more R 3a is optionally substituted with

[0125] In some embodiments, R 3 is NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), or N(C1-C6 alkyl)2.

[0126] In some embodiments, R 3is NH2.

[0127] In some embodiments, R 3 is one or more R 3a is —NH(C1-C6 alkyl) optionally substituted with

[0128] In some embodiments, R 3 is —NH(C1-C6 alkyl).

[0129] In some embodiments, R 3 is one or more R 3a is —NHC(═O)(C1-C6 haloalkyl) optionally substituted with

[0130] In some embodiments, R 3 is —NHC(═O)(C1-C6 haloalkyl).

[0131] In some embodiments, R 3 is one or more R 3a is —NHC(═O)O(C1-C6 alkyl) optionally substituted with

[0132] In some embodiments, R 3 is —NHC(═O)O(C1-C6 alkyl).

[0133] In some embodiments, R 3 is one or more R 3a is N(C1-C6 alkyl)2 optionally substituted with

[0134] In some embodiments, R 3 is N(C1-C6 alkyl)2.

[0135] In some embodiments, R 3is -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), or -C(=O)O(C1-C6 alkyl), and the -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), or -C(=O)O(C1-C6 alkyl) is selected from the group consisting of one or more R 3a is optionally substituted with

[0136] In some embodiments, R 3 is —S(═O)2—(C1-C6 alkyl), —C(═O)H, —C(═O)(C1-C6 alkyl), or —C(═O)O(C1-C6 alkyl).

[0137] In some embodiments, R 3 is one or more R 3a is —S(═O)2—(C1-C6 alkyl) optionally substituted with

[0138] In some embodiments, R 3 is -S(=O)2-(C1-C6 alkyl).

[0139] In some embodiments, R 3 is -C(=O)H.

[0140] In some embodiments, R 3 is one or more R 3a is —C(═O)(C1-C6 alkyl) optionally substituted with

[0141] In some embodiments, R 3 is —C(═O)(C1-C6 alkyl).

[0142] In some embodiments, R 3 is one or more R 3a is —C(═O)O(C1-C6 alkyl) optionally substituted with

[0143] In some embodiments, R 3is —C(═O)O(C1-C6 alkyl).

[0144] In some embodiments, R 3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl, or 5-10-membered heteroaryl, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a is optionally substituted with

[0145] In some embodiments, R 3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 It is aryl or 5- to 10-membered heteroaryl.

[0146] In some embodiments, R 3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy is selected from the group consisting of one or more R 3a is optionally substituted with

[0147] In some embodiments, R 3is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0148] In some embodiments, R 3 is one or more R 3a is C1-C6 alkyl optionally substituted with

[0149] In some embodiments, R 3 is one or more R 3a is a C2-C6 alkenyl optionally substituted with

[0150] In some embodiments, R 3 is C2-C6 alkenyl.

[0151] In some embodiments, R 3 is one or more R 3a is a C2-C6 alkynyl optionally substituted with

[0152] In some embodiments, R 3 is C2-C6 alkynyl.

[0153] In some embodiments, R 3 is one or more R 3a is C1-C6 alkoxy optionally substituted with

[0154] In some embodiments, R 3 is C1-C6 alkoxy.

[0155] In some embodiments, R 3 is C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl or 5-10 membered heteroaryl, and the C3-C 12 Cycloalkyl, C3-C 12Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a is optionally substituted with

[0156] In some embodiments, R 3 is C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 It is aryl or 5- to 10-membered heteroaryl.

[0157] In some embodiments, R 3 is one or more R 3a C3-C optionally substituted with 12 It is cycloalkyl.

[0158] In some embodiments, R 3 is C3-C 12 It is cycloalkyl.

[0159] In some embodiments, R 3 is one or more R 3a C3-C optionally substituted with 12 It is a cycloalkenyl.

[0160] In some embodiments, R 3 is C3-C 12 It is a cycloalkenyl.

[0161] In some embodiments, R 3 is one or more R 3a is a 3- to 12-membered heterocycloalkyl optionally substituted with

[0162] In some embodiments, R 3 is a 3- to 12-membered heterocycloalkyl.

[0163] In some embodiments, R3 is one or more R 3a and optionally substituted 3- to 12-membered heterocycloalkenyl.

[0164] In some embodiments, R 3 is a 3- to 12-membered heterocycloalkenyl.

[0165] In some embodiments, R 3 is one or more R 3a C6-C optionally substituted with 10 It is aryl.

[0166] In some embodiments, R 3 is C6-C 10 It is aryl.

[0167] In some embodiments, R 3 is one or more R 3a is a 5-10 membered heteroaryl optionally substituted with

[0168] In some embodiments, R 3 is a 5-10 membered heteroaryl.

[0169] In some embodiments, R 3 is halogen, cyano, or C1-C6 alkyl.

[0170] In some embodiments, R 3 is a halogen. In some embodiments, R 3 is F or Cl.

[0171] In some embodiments, R 3 is F. In some embodiments, R 3 is Cl.

[0172] In some embodiments, R 3 is cyano.

[0173] In some embodiments, R 3is C1-C6 alkyl. In some embodiments, R 3 is CH3.

[0174] In some embodiments, each R 3a are independently halogen, cyano, oxo, -OH, NH2, -NH(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl, and the above-mentioned -NH(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 The aryl or 5-10 membered heteroaryl is optionally substituted with one or more halogens.

[0175] In some embodiments, each R 3a are independently halogen, cyano, oxo, -OH, NH2, -NH(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the NHC(=O)O(C1-C6 alkyl) is optionally substituted with one or more halogens.

[0176] In some embodiments, each R 3a are independently halogen, cyano, oxo, —OH, NH, —NH(C-C alkyl), —NHC(═O)O(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)(C-C alkyl), or —C(═O)O(C-C alkyl), wherein the NHC(═O)O(C-C alkyl) is optionally substituted with one or more halogens.

[0177] In some embodiments, each R 3a is independently halogen, cyano, oxo, or —OH.

[0178] In some embodiments, each R 3a is independently halogen. In some embodiments, each R 3a is independently cyano. In some embodiments, each R 3a is independently oxo. In some embodiments, each R 3a are independently —OH.

[0179] In some embodiments, each R 3a are independently NH, —NH(C-C alkyl), —NHC(═O)O(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)(C-C alkyl), or —C(═O)O(C-C alkyl), wherein —NHC(═O)O(C-C alkyl) is optionally substituted with one or more halogens.

[0180] In some embodiments, each R 3a are independently NH2.

[0181] In some embodiments, each R 3a are independently —NH(C1-C6 alkyl).

[0182] In some embodiments, each R 3ais independently —NHC(═O)O(C1-C6 alkyl) optionally substituted with one or more halogens.

[0183] In some embodiments, each R 3a are independently —NHC(═O)O(C1-C6 alkyl).

[0184] In some embodiments, each R 3a are independently N(C1-C6 alkyl)2.

[0185] In some embodiments, each R 3a are independently -S(=O)2-(C1-C6 alkyl).

[0186] In some embodiments, each R 3a are independently —C(═O)(C1-C6 alkyl).

[0187] In some embodiments, each R 3a are independently —C(═O)O(C1-C6 alkyl).

[0188] In some embodiments, each R 3a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy.

[0189] In some embodiments, each R 3a are independently C1-C6 alkyl.

[0190] In some embodiments, each R 3a are independently C2-C6 alkenyl.

[0191] In some embodiments, each R 3a are independently C2-C6 alkynyl.

[0192] In some embodiments, each R 3a are independently C1-C6 alkoxy.

[0193] In some embodiments, each R 3a independently, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 It is aryl or 5- to 10-membered heteroaryl.

[0194] In some embodiments, each R 3a independently, C3-C 12 It is cycloalkyl.

[0195] In some embodiments, each R 3a is independently 3 to 12 membered heterocycloalkyl.

[0196] In some embodiments, each R 3a independently, C6-C 10 It is aryl.

[0197] In some embodiments, each R 3a is independently 5-10 membered heteroaryl.

[0198] In some embodiments, R 4 is H.

[0199] In some embodiments, R 4 is halogen, cyano, or C1-C6 alkyl.

[0200] In some embodiments, R 4 is a halogen. In some embodiments, R 4 is F or Cl.

[0201] In some embodiments, R 4 is F. In some embodiments, R 4 is Cl.

[0202] In some embodiments, R 4 is cyano.

[0203] In some embodiments, R 4is C1-C6 alkyl. In some embodiments, R 4 is CH3.

[0204] In some embodiments, R 5 is H.

[0205] In some embodiments, R 5 is halogen, cyano, or C1-C6 alkyl.

[0206] In some embodiments, R 5 is a halogen. In some embodiments, R 5 is F or Cl.

[0207] In some embodiments, R 5 is F. In some embodiments, R 5 is Cl.

[0208] In some embodiments, R 5 is cyano.

[0209] In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is CH3.

[0210] In some embodiments, R 6 is H.

[0211] In some embodiments, R 6 is halogen, cyano, or C1-C6 alkyl.

[0212] In some embodiments, R 6 is a halogen. In some embodiments, R 6 is F or Cl.

[0213] In some embodiments, R 6 is F. In some embodiments, R 6 is Cl.

[0214] In some embodiments, R 6 is cyano.

[0215] In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is CH3.

[0216] Variables Y, Z, R Z , R Za , and R Zb In some embodiments, Y is absent, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl is selected from the group consisting of one or more of halogen, oxo, cyano, —OH, NH, —NH(C1-C6 alkyl)—OH, C1-C6 alkyl, C2-C6 alkenyl, —(C1-C6 alkyl)(C6-C 10 C1-C6 alkoxy optionally substituted with aryl, or C3-C 12 Optionally substituted with cycloalkyl.

[0217] In some embodiments, Y is absent.

[0218] In some embodiments, Y is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl is selected from the group consisting of one or more of halogen, oxo, cyano, —OH, NH2, —NH(C1-C6 alkyl)—OH, C1-C6 alkyl, C2-C6 alkenyl, —(C1-C6 alkyl)(C6-C 10 C1-C6 alkoxy optionally substituted with aryl, or C3-C 12 Optionally substituted with cycloalkyl.

[0219] In some embodiments, Y is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy.

[0220] In some embodiments, Y is C1-C6 alkyl optionally substituted with one or more halogen, oxo, cyano, -OH, NH2, -NH(C1-C6 alkyl)-OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyl.

[0221] In some embodiments, Y is C1-C6 alkyl. In some embodiments, Y is -CH2-.

[0222] In some embodiments, Y is C1-C6 alkyl optionally substituted with one or more oxo, cyano, or -OH.

[0223] In some embodiments, Y is C1-C6 alkyl optionally substituted with one or more oxo.

[0224] In some embodiments, Y is C1-C6 alkyl substituted with one or more oxo.

[0225] In some embodiments, Y is methyl optionally substituted with one or more oxo.

[0226] In some embodiments, Y is methyl-substituted oxo, ie, Y is -C(=O)-.

[0227] In some embodiments, Y is C1-C6 alkyl optionally substituted with one or more cyano.

[0228] In some embodiments, Y is C1-C6 alkyl substituted with one or more cyano.

[0229] In some embodiments, Y is methyl optionally substituted with one or more cyano.

[0230] In some embodiments, Y is C1-C6 alkyl optionally substituted with one or more -OH.

[0231] In some embodiments, Y is C1-C6 alkyl substituted with one or more -OH.

[0232] In some embodiments, Z is H.

[0233] In some embodiments, Z is C-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl or 5-10 membered heteroaryl, and the C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R Z is optionally substituted with

[0234] In some embodiments, Z is C-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 It is aryl or 5- to 10-membered heteroaryl.

[0235] In some embodiments, Z is one or more R Z C3-C optionally substituted with 12 It is cycloalkyl.

[0236] In some embodiments, Z is C-C 12 It is cycloalkyl.

[0237] In some embodiments, Z is one or more R Z C3-C optionally substituted with 12 It is a cycloalkenyl.

[0238] In some embodiments, Z is C-C 12 It is a cycloalkenyl.

[0239] In some embodiments, Z is one or more R Z is a 3- to 12-membered heterocycloalkyl optionally substituted with

[0240] In some embodiments, Z is a 3-12 membered heterocycloalkyl.

[0241] In some embodiments, Z is one or more R Z and optionally substituted 3- to 12-membered heterocycloalkenyl.

[0242] In some embodiments, Z is a 3-12 membered heterocycloalkenyl.

[0243] In some embodiments, Z is one or more R Z C6-C optionally substituted with 10 It is aryl.

[0244] In some embodiments, Z is C-C 10 It is aryl.

[0245] In some embodiments, Z is one or more R Z is a 5-10 membered heteroaryl optionally substituted with

[0246] In some embodiments, Z is a 5-10 membered heteroaryl.

[0247] In some embodiments, Z is C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is selected from the group consisting of one or more R Z is optionally substituted with

[0248] In some embodiments, Z is C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl.

[0249] In some embodiments, Z is C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl is selected from the group consisting of one or more R Z is replaced by .

[0250] In some embodiments, Z is one or more R Z is a C3-C8 cycloalkyl optionally substituted with

[0251] In some embodiments, Z is C3-C8 cycloalkyl.

[0252] In some embodiments, Z is one or more R Z is a C3-C8 cycloalkyl substituted with

[0253] In some embodiments, Z is one or more R Z is cyclopropyl optionally substituted with

[0254] In some embodiments, Z is one or more R Z is cyclobutyl optionally substituted with

[0255] In some embodiments, Z is one or more R Z and cyclohexyl optionally substituted with

[0256] In some embodiments, Z is one or more R Z is a 3- to 8-membered heterocycloalkyl optionally substituted with

[0257] In some embodiments, Z is a 3-8 membered heterocycloalkyl.

[0258] In some embodiments, Z is one or more R Z is a 3- to 8-membered heterocycloalkyl substituted with

[0259] In some embodiments, Z is azetidinyl or oxetanyl, and the azetidinyl or oxetanyl is selected from the group consisting of one or more R Z is optionally substituted with

[0260] In some embodiments, Z is azetidinyl or oxetanyl.

[0261] In some embodiments, Z is azetidinyl or oxetanyl, and the azetidinyl or oxetanyl is selected from the group consisting of one or more R Z is replaced by .

[0262] In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl, wherein the pyrrolidinyl or tetrahydrofuranyl is selected from the group consisting of one or more R Z is optionally substituted with

[0263] In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl.

[0264] In some embodiments, Z is pyrrolidinyl or tetrahydrofuranyl, wherein the pyrrolidinyl or tetrahydrofuranyl is selected from the group consisting of one or more R Z is replaced by .

[0265] In some embodiments, Z is piperidinyl or tetrahydropyranyl, wherein the piperidinyl or tetrahydropyranyl is selected from the group consisting of one or more R Z is optionally substituted with

[0266] In some embodiments, Z is piperidinyl or tetrahydropyranyl.

[0267] In some embodiments, Z is piperidinyl or tetrahydropyranyl, wherein the piperidinyl or tetrahydropyranyl is selected from the group consisting of one or more R Z is replaced by

[0268] In some embodiments, each R Zare independently oxo, halogen, cyano, -OH, ═NR Za , NH2, NHR Za , NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(=O)(=NR Za )-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl, a 3- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za is optionally substituted with

[0269] In some embodiments, each R Z are independently oxo, halogen, cyano, -OH, ═NR Za , NH2, NHR Za , NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(=O)(=NR Za )-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za, -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 It is cycloalkyl, 3- to 12-membered heterocycloalkyl, or 5- to 10-membered heteroaryl.

[0270] In some embodiments, each R Z are independently oxo, halogen, cyano, or —OH.

[0271] In some embodiments, each R Z are independent, R Z is oxo.

[0272] In some embodiments, each R Z are independent, R Z is halogen. In some embodiments, each R Z are independently F or Cl.

[0273] In some embodiments, each R Z is independently F. In some embodiments, each R Z are independently Cl.

[0274] In some embodiments, each R Z is independently cyano. In some embodiments, each R Z are independently —OH.

[0275] In some embodiments, each R Z are independent, =NR Za In some embodiments, each R Z independently, NHR Za is.

[0276] In some embodiments, each R Z are independently NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more RZa is optionally substituted with

[0277] In some embodiments, each R Z are independently NH2.

[0278] In some embodiments, each R Z are independently NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Za is optionally substituted with

[0279] In some embodiments, each R Z are independently NH(C1-C6 alkyl), or N(C1-C6 alkyl)2.

[0280] In some embodiments, each R Z are independently NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Za is replaced by .

[0281] In some embodiments, each R Z independently, one or more R Za is —S(═O)2—(C1-C6 alkyl) optionally substituted with

[0282] In some embodiments, each R Z are independently -S(=O)2-(C1-C6 alkyl).

[0283] In some embodiments, each R Z are independently -S(=O)2-CH3.

[0284] In some embodiments, each R Z independently, one or more R Za is —S(C1-C6 alkyl) optionally substituted with

[0285] In some embodiments, each R Z independently, one or more R Za is —S(C1-C6 alkyl) substituted with

[0286] In some embodiments, each R Z are independently —S(C1-C6 alkyl).

[0287] In some embodiments, each R Z independently, one or more R Za -S(=NR Za )-(C1-C6 alkyl).

[0288] In some embodiments, each R Z independently, one or more R Za -S(=NR Za )-(C1-C6 alkyl).

[0289] In some embodiments, each R Z are independent, -S(=NR Za )-(C1-C6 alkyl).

[0290] In some embodiments, each R Z independently, one or more R Za is —S(C2-C6 alkenyl) optionally substituted with

[0291] In some embodiments, each R Z independently, one or more R Za is —S(C2-C6 alkenyl) substituted with

[0292] In some embodiments, each R Z are independently —S(C2-C6 alkenyl).

[0293] In some embodiments, at least one R Zis —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl), and the —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl) is selected from the group consisting of one or more R Za is optionally substituted with

[0294] In some embodiments, each R Z are independently —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl).

[0295] In some embodiments, each R Z are independently —C(═O)—(C1-C6 alkyl).

[0296] In some embodiments, each R Z are independently —C(═O)—(C1-C6 alkyl).

[0297] In some embodiments, each R Z are independently —C(═O)—CH═CH2.

[0298] In some embodiments, each R Z are independently —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl), and the —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl) is selected from the group consisting of one or more R Za is replaced by .

[0299] In some embodiments, each R Z are independently -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), or -C(=O)-(C1-C6 alkoxyl), and the above -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za, -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), or -C(=O)-(C1-C6 alkoxyl) is one or more R Za is optionally substituted with

[0300] In some embodiments, each R Z are independently -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za , -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl) or -C(=O)-(C1-C6 alkoxyl).

[0301] In some embodiments, each R Z independently, one or more R Za is —S(═O)2—(C2-C6 alkenyl) optionally substituted with

[0302] In some embodiments, each R Z are independently -S(=O)2-(C2-C6 alkenyl).

[0303] In some embodiments, each R Z independently, one or more R Za is —C(═O)(3-12 membered heterocycloalkyl) optionally substituted with

[0304] In some embodiments, each R Z are independently —C(═O)(3-12 membered heterocycloalkyl).

[0305] In some embodiments, each R Z independently, one or more R Za is —C(═O)NH(C1-C6 alkyl) optionally substituted with

[0306] In some embodiments, each R Z are independently —C(═O)NH(C1-C6 alkyl).

[0307] In some embodiments, each R Z are independently -C(=O)NR Za is.

[0308] In some embodiments, each R Z independently, one or more R Za is —C(═O)—(C1-C6 alkyl) optionally substituted with

[0309] In some embodiments, each R Z are independently C(=O)-(C1-C6 alkyl).

[0310] In some embodiments, each R Z independently, one or more R Za C(=O)-(C2-C6 alkenyl) optionally substituted with

[0311] In some embodiments, each R Z are independently —C(═O)—(C2-C6 alkenyl).

[0312] In some embodiments, each R Z independently, one or more R Za is —C(═O)—(C1-C6 alkoxyl) optionally substituted with

[0313] In some embodiments, each R Z are independently —C(═O)—(C1-C6 alkoxyl).

[0314] In some embodiments, each R Z independently, one or more R Za is a 5-10 membered heteroaryl optionally substituted with

[0315] In some embodiments, each R Z is independently 5-10 membered heteroaryl.

[0316] In some embodiments, each R Zare independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl is selected from the group consisting of one or more R Za is optionally substituted with

[0317] In some embodiments, each R Z independently, one or more R Za is C1-C6 alkyl optionally substituted with

[0318] In some embodiments, each R Z are independently C1-C6 alkyl.

[0319] In some embodiments, each R Z independently, one or more R Za is a C1-C6 alkyl substituted with

[0320] In some embodiments, each R Z independently, one or more R Za is a C2-C6 alkenyl optionally substituted with

[0321] In some embodiments, each R Z are independently C2-C6 alkenyl.

[0322] In some embodiments, each R Z independently, one or more R Za and C2-C6 alkenyl substituted with

[0323] In some embodiments, each R Z independently, one or more R Za is a C2-C6 alkynyl optionally substituted with

[0324] In some embodiments, each R Z are independently C2-C6 alkynyl.

[0325] In some embodiments, each RZ independently, one or more R Za is a C2-C6 alkynyl substituted with

[0326] In some embodiments, each R Z independently, one or more R Za is C1-C6 alkoxyl optionally substituted with

[0327] In some embodiments, each R Z are independently C1-C6 alkoxyl.

[0328] In some embodiments, each R Z independently, one or more R Za is a C1-C6 alkoxyl substituted with

[0329] In some embodiments, each R Z independently, C3-C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, and the C3-C 12 A cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R Za is optionally substituted with

[0330] In some embodiments, each R Z are independently C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Za is optionally substituted with

[0331] In some embodiments, each R Z independently, one or more R Za C3-C optionally substituted with 12 It is cycloalkyl.

[0332] In some embodiments, each R Z independently, C3-C 12 It is cycloalkyl.

[0333] In some embodiments, each R Z independently, one or more R Za C3-C substituted with 12 It is cycloalkyl.

[0334] In some embodiments, each R Z independently, one or more R Za is a C3-C8 cycloalkyl optionally substituted with

[0335] In some embodiments, each R Z is independently C3-C8 cycloalkyl.

[0336] In some embodiments, each R Z independently, one or more R Za is a C3-C8 cycloalkyl substituted with

[0337] In some embodiments, each R Z independently, one or more R Za is a 3- to 12-membered heterocycloalkyl optionally substituted with

[0338] In some embodiments, each R Z is independently 3 to 12 membered heterocycloalkyl.

[0339] In some embodiments, each R Z independently, one or more R Za is a 3- to 12-membered heterocycloalkyl substituted with

[0340] In some embodiments, each R Z independently, one or more R Za is a 3- to 8-membered heterocycloalkyl optionally substituted with

[0341] In some embodiments, each R Z is independently 3 to 8 membered heterocycloalkyl.

[0342] In some embodiments, each R Zindependently, one or more R Za is a 3- to 8-membered heterocycloalkyl substituted with

[0343] In some embodiments, each R Za are independently H, oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 Cycloalkyl, or 3-12-membered heterocycloalkyl, and the above-mentioned NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R Zb is optionally substituted with

[0344] Each R Za are independently H, oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 It is a cycloalkyl, or a 3- to 12-membered heterocycloalkyl.

[0345] In some embodiments, each R Za are independently H.

[0346] In some embodiments, each R Za are independently oxo, halogen, cyano, or —OH.

[0347] In some embodiments, each R Za are independently oxo.

[0348] In some embodiments, each R Za is independently halogen. In some embodiments, each R Za are independently F or Cl.

[0349] In some embodiments, each R Za is independently F. In some embodiments, each R Za are independently Cl.

[0350] In some embodiments, each R Za are independently cyano.

[0351] In some embodiments, each R Za are independently —OH.

[0352] In some embodiments, each R Za are independently NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Zb is optionally substituted with

[0353] In some embodiments, each R Za are independently NH2.

[0354] In some embodiments, each R Za are independently NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Zb is optionally substituted with

[0355] In some embodiments, each R Za are independently NH(C1-C6 alkyl), or N(C1-C6 alkyl)2.

[0356] In some embodiments, each RZa are independently NH(C1-C6 alkyl) or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Zb is replaced by .

[0357] In some embodiments, each R Za independently, one or more R Zb is —S(═O)2—(C1-C6 alkyl) optionally substituted with

[0358] In some embodiments, each R Za are independently -S(=O)2-(C1-C6 alkyl).

[0359] In some embodiments, each R Za are independently -S(=O)2-CH3.

[0360] In some embodiments, each R Za independently, one or more R Zb is -S(=O)2-(C1-C6 alkyl) substituted with

[0361] In some embodiments, each R Za are independently —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl), and the —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl) is selected from the group consisting of one or more R Zb is optionally substituted with

[0362] In some embodiments, each R Za are independently —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl).

[0363] In some embodiments, each R Za are independently —C(═O)—(C1-C6 alkyl).

[0364] In some embodiments, each R Zaare independently —C(═O)—(C1-C6 alkyl).

[0365] In some embodiments, each R Za are independently —C(═O)—CH═CH2.

[0366] In some embodiments, each R Za are independently —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl), and the —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl) is selected from the group consisting of one or more R Zb is replaced by

[0367] In some embodiments, each R Za are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl is selected from the group consisting of one or more R Zb is optionally substituted with

[0368] In some embodiments, each R Za independently, one or more R Zb is C1-C6 alkyl optionally substituted with

[0369] In some embodiments, each R Za are independently C1-C6 alkyl.

[0370] In some embodiments, each R Za independently, one or more R Zb is a C1-C6 alkyl substituted with

[0371] In some embodiments, each R Za independently, one or more R Zb is a C2-C6 alkenyl optionally substituted with

[0372] In some embodiments, each R Zaare independently C2-C6 alkenyl.

[0373] In some embodiments, each R Za independently, one or more R Zb and C2-C6 alkenyl substituted with

[0374] In some embodiments, each R Za independently, one or more R Zb is a C2-C6 alkynyl optionally substituted with

[0375] In some embodiments, each R Za are independently C2-C6 alkynyl.

[0376] In some embodiments, each R Za independently, one or more R Zb is a C2-C6 alkynyl substituted with

[0377] In some embodiments, each R Za independently, one or more R Zb is C1-C6 alkoxyl optionally substituted with

[0378] In some embodiments, each R Za are independently C1-C6 alkoxyl.

[0379] In some embodiments, each R Za independently, one or more R Zb is a C1-C6 alkoxyl substituted with

[0380] In some embodiments, each R Za independently, C3-C 12 cycloalkyl or 3- to 12-membered heterocycloalkyl, and the C3-C 12 A cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R Zb is optionally substituted with

[0381] In some embodiments, each RZa independently, one or more R Zb C3-C optionally substituted with 12 It is cycloalkyl.

[0382] In some embodiments, each R Za independently, C3-C 12 It is cycloalkyl.

[0383] In some embodiments, each R Za independently, one or more R Zb C3-C substituted with 12 It is cycloalkyl.

[0384] In some embodiments, each R Za independently, one or more R Zb is a 3- to 12-membered heterocycloalkyl optionally substituted with

[0385] In some embodiments, each R Za is independently 3 to 12 membered heterocycloalkyl.

[0386] In some embodiments, each R Za independently, one or more R Zb is a 3- to 12-membered heterocycloalkyl substituted with

[0387] In some embodiments, each R Za are independently C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Zb is optionally substituted with

[0388] In some embodiments, each R Za independently, one or more R Zb is a C3-C8 cycloalkyl optionally substituted with

[0389] In some embodiments, each R Za is independently C3-C8 cycloalkyl.

[0390] In some embodiments, each R Za independently, one or more R Zb is a C3-C8 cycloalkyl substituted with

[0391] In some embodiments, each R Za independently, one or more R Zb is a 3- to 8-membered heterocycloalkyl optionally substituted with

[0392] In some embodiments, each R Za is independently 3 to 8 membered heterocycloalkyl.

[0393] In some embodiments, each R Za independently, one or more R Zb is a 3- to 8-membered heterocycloalkyl substituted with

[0394] In some embodiments, each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0395] In some embodiments, each R Zb is independently oxo, halogen, cyano, or —OH.

[0396] In some embodiments, each R Zb are independently oxo.

[0397] In some embodiments, each R Zb is independently halogen. In some embodiments, each R Zb are independently F or Cl.

[0398] In some embodiments, each RZb is independently F. In some embodiments, each R Zb are independently Cl.

[0399] In some embodiments, each R Zb is independently cyano. In some embodiments, each R Zb are independently —OH.

[0400] In some embodiments, each R Zb is independently NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2.

[0401] In some embodiments, each R Zb are independently NH2.

[0402] In some embodiments, each R Zb are independently NH(C1-C6 alkyl).

[0403] In some embodiments, each R Zb are independently N(C1-C6 alkyl)2.

[0404] In some embodiments, each R Zb are independently -S(=O)2-(C1-C6 alkyl).

[0405] In some embodiments, each R Zb are independently —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl).

[0406] In some embodiments, each R Zb are independently —C(═O)—(C1-C6 alkyl).

[0407] In some embodiments, each R Zb are independently —C(═O)—(C2-C6 alkenyl).

[0408] In some embodiments, each R Zbare independently —C(═O)—CH═CH2.

[0409] In some embodiments, each R Zb is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl.

[0410] In some embodiments, each R Zb are independently C1-C6 alkyl.

[0411] In some embodiments, each R Zb are independently C2-C6 alkenyl.

[0412] In some embodiments, each R Zb are independently C2-C6 alkynyl.

[0413] In some embodiments, each R Zb are independently C1-C6 alkoxyl.

[0414] Exemplary Embodiments of the Compound In some embodiments, the compound is a compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0415] In some embodiments, the compound is a compound of formula (Ia), (Ib), (Ic), or (Id): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0416] In some embodiments, the compound is a compound of formula (II): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0417] In some embodiments, the compound is a compound of the following formula (II-a), (II-b), (II-c), or (II-d): [ka] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0418] In some embodiments, the compound is a compound set forth in Table I and Table II, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0419] In some embodiments, the compound is a compound set forth in Table I and Table II, or a pharmaceutically acceptable salt thereof.

[0420] In some embodiments, the compound is a compound described in Table I and Table II.

[0421] In some embodiments, the compound is a compound set forth in Table II, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0422] In some embodiments, the compound is a compound set forth in Table II, or a pharmaceutically acceptable salt thereof.

[0423] In some embodiments, the compound is a compound set forth in Table II.

[0424] In some embodiments, the compound is a compound set forth in Table I, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0425] In some embodiments, the compound is a compound set forth in Table I, or a pharmaceutically acceptable salt thereof.

[0426] In some embodiments, the compound is a compound set forth in Table I. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

[0427] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0428] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I and Table II, or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I and Table II.

[0430] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I, or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table I.

[0432] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table II, or a pharmaceutically acceptable salt thereof.

[0433] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table II.

[0434] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein, substituting an isotopic-labeled reagent for a non-isotopically labeled reagent.

[0435] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0436] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0437] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table I and Table II, or a pharmaceutically acceptable salt thereof.

[0438] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table I and Table II.

[0439] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table I, or a pharmaceutically acceptable salt thereof.

[0440] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table I.

[0441] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table II, or a pharmaceutically acceptable salt thereof.

[0442] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds set forth in Table II.

[0443] A deuterium-labeled compound is understood to contain deuterium atoms having a deuterium abundance that is much greater than the natural abundance of deuterium, which is 0.015%.

[0444] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio between the abundance of deuterium and the natural abundance of deuterium.

[0445] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein, substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0446] Compounds of the present invention containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. 2 Substitution with H) may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0447] For the avoidance of doubt, when a group is modified herein by "as described herein," it is to be understood that the group includes the broadest definition appearing first, as well as each and every specific definition for that group.

[0448] Suitable pharmaceutically acceptable salts of compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, for example, acid addition salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, triethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0449] It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0450] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0451] As used herein, the term "chiral center" refers to a carbon atom bonded to four non-identical substituents.

[0452] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds with two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0453] As used herein, the term "geometric isomer" refers to diastereomers whose presence hinders rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0454] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. When a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and it is understood that the naming of the compound does not exclude any isomeric form, and it is understood that not all isomers may have the same level of activity.

[0455] It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof, and it is also understood that not all atropisomers have the same level of activity.

[0456] As used herein, "atropisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. In atropisomers, the presence of atropisomers restricts rotation by preventing the rotation of large groups around a central bond. However, such atropisomers usually exist as a mixture, but as a result of recent advances in chromatography technology, it has been possible to separate a mixture of two atropisomers when selected.

[0457] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This conversion results in the formal migration of a hydrogen atom accompanied by the interchange of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomeric sets in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which the simultaneous shift of electrons and hydrogen atoms occurs. Cyclic-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to give a cyclic (ring-like) form, such as that exhibited by glucose.

[0458] It is understood that the compounds of the present application may be represented as different tautomeric forms. It should also be understood that, if a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present application, and the name of the compound does not exclude any tautomeric form. It will be understood that certain tautomeric forms may have higher activity levels than others.

[0459] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, if a compound has an asymmetric center and is bonded to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0460] The compounds of the present disclosure may have one or more asymmetric centers, and therefore, such compounds can be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and their racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or resolution of racemates. Some of the compounds of the present disclosure may have geometric isomeric centers (E and Z isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0461] The present disclosure also includes compounds of the present disclosure, as defined herein, that contain one or more isotopic substitutions.

[0462] It is understood that the compounds of any formula described herein include, where applicable, the compounds themselves as well as their pharmaceutically acceptable salts and solvates. Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetic acid, glutamate, glucuronic acid, glutaric acid, malate, maleate, succinate, fumarate, tartaric acid, tosylate, salicylate, lactic acid, naphthalenesulfonate, and acetate (e.g., trifluoroacetic acid).

[0463] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts may also be formed between a cation and a negatively charged group (e.g., carboxylic acid) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0464] It is understood that the compounds of the present disclosure, such as salts of the compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvates and acetone solvates.

[0465] As used herein, "solvate" refers to a solvent addition form that contains either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by trapping a certain molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as HO.

[0466] As used herein, the term "analog" refers to a compound that is structurally similar to another but differs slightly in composition (such as by replacing one atom with an atom of a different element, or by the presence of a particular functional group, or by replacing one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not in structure or origin.

[0467] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0468] As used herein, the term "bioisostere" refers to a compound resulting from the exchange of one atom or group of atoms with another broadly similar atom or group of atoms. The purpose of bioisostere substitution is to create a new compound with similar biological properties to the parent compound. Bioisostere substitution may be physicochemical or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0469] It should also be understood that certain compounds of the present disclosure can exist in solvated and unsolvated forms, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0470] It should also be understood that certain compounds of the present disclosure may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline substances can be analyzed using conventional techniques, such as powder X-ray diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline substances can be determined by Karl Fischer analysis.

[0471] The compounds of the present disclosure may exist in many different tautomeric forms, and reference to a compound of the present disclosure includes all such forms. For the avoidance of doubt, even if a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are encompassed by Formula (I). Examples of tautomers include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro. [ka]

[0472] Compounds of the present disclosure containing an amine functional group can also form N-oxides. Reference herein to compounds disclosed herein containing an amine functional group also includes N-oxides. When a compound contains multiple amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or the N-oxides of nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977-1980. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with metachloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0473] The compounds of the present disclosure may be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present disclosure. Prodrugs may be used to modify the physical and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs may be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be added. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents on the sulfonylurea group in the compounds of any one of the formulas disclosed herein.

[0474] Thus, the present disclosure includes the compounds of the present disclosure as previously defined when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure also includes compounds of the present disclosure produced by organic synthetic means, as well as compounds produced in the human or animal body by metabolism of a precursor compound, i.e., the compounds of the present disclosure may be synthetically produced compounds or metabolically produced compounds.

[0475] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. For example, various forms of prodrugs are described in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al. al., Chem.Pharm.Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14, and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0476] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of the compounds of the present disclosure containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C1-C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Alkanoyl groups, such as C1-C6 alkyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. 10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0477] Suitable pharmaceutically acceptable prodrugs of compounds of the present disclosure having a carboxy group include, for example, in vivo cleavable amides thereof, e.g., amines such as ammonia, C, e.g., methylamine, etc. 1-4 amides formed with amines such as alkylamines, for example (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[0478] Suitable pharmaceutically acceptable prodrugs of the disclosed compounds having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C2 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Included are amides formed with alkanoyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0479] The in vivo effects of the compounds of the present disclosure may be exerted in part by one or more metabolic products formed in the human or animal body after administration of the compounds of the present disclosure. As previously described herein, the in vivo effects of the compounds of the present disclosure may also be exerted by metabolism of precursor compounds (prodrugs).

[0480] Synthesis method In some aspects, the disclosure provides methods of preparing the compounds disclosed herein.

[0481] In some aspects, the disclosure provides methods of preparing compounds, comprising one or more of the steps described herein.

[0482] In some aspects, the disclosure provides compounds obtainable by, obtained by, or obtained directly by the methods for preparing the compounds described herein.

[0483] In some aspects, the present disclosure provides intermediates suitable for use in the methods for preparing the compounds described herein.

[0484] The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying examples.

[0485] In the description of synthetic methods described herein, and in any referenced synthetic methods used to prepare starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and work-up procedures, can be selected by one skilled in the art.

[0486] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0487] It will be understood that during the synthesis of the compounds of the present disclosure or during the synthesis of certain starting materials in the processes defined herein, it may be desirable to protect certain substituents to prevent their undesired reactions. A skilled chemist will understand when such protection is necessary and how to place and subsequently remove such protecting groups. For examples of protecting groups, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any conventional method described in the literature or known to skilled chemists that is appropriate for the removal of the protecting group in question, and such methods will be selected to provide for the removal of the protecting group with minimal interference with groups elsewhere in the molecule. Thus, when reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0488] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium on carbon, or by treatment with a Lewis acid, e.g., boron tris(trifluoroacetic acid). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0489] Suitable protecting groups for hydroxy groups include, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis using a suitable base such as an alkali metal hydroxide, e.g., lithium, sodium, or ammonia hydroxide. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation over a catalyst such as palladium on carbon.

[0490] Suitable protecting groups for carboxy groups are, for example, esterifying groups, for example, a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example, a tert-butyl group which may be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example, a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0491] Once a compound of the present disclosure has been synthesized by any one of the processes defined herein, the process may then further comprise the following additional steps: (i) removing any protecting groups present, (ii) converting the compound of the present disclosure into another compound of the present disclosure, (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof, and / or (iv) forming a prodrug thereof.

[0492] The resulting compounds of this disclosure can be isolated and purified using techniques well known in the art.

[0493] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the above solvents, or mixtures with water.

[0494] The reaction temperature is preferably between about -100°C and 300°C, depending on the reaction step and conditions used.

[0495] The reaction time generally ranges from a few minutes to several days, depending on the reactivity of the respective compounds and the respective reaction conditions. The appropriate reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature described above, the suitable reaction time is generally in the range of 10 minutes to 48 hours.

[0496] Moreover, by utilizing the procedures described herein in conjunction with procedures in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0497] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are readily accessible by a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize which types of reagents and reaction conditions to use to obtain the compounds of the present disclosure, and how they should be applied and adapted whenever necessary or useful in any particular case. Furthermore, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, e.g., by converting one particular functional group present in a compound of the present disclosure or a suitable precursor molecule thereof into another by applying standard synthetic methods such as reduction, oxidation, addition, or substitution reactions, which are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or protecting) groups whenever necessary or useful; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.W. Huts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis," 4th edition (2006) (John Wiley & Sons).

[0498] General routes for the preparation of compounds of the present application are described in Scheme 1 and Scheme 2. [ka] [ka]

[0499] Biological assays Once compounds designed, selected, and / or optimized by the above-described methods are produced, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0500] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0501] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the disclosed compounds, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0502] In some embodiments, the biological assay evaluates the ability of a compound to inhibit cell proliferation.

[0503] In some embodiments, cells (e.g., SNU-16 (FGFR2-amplified) cells) can be suspended and dispensed into plates. In some embodiments, cells (e.g., UM-UC-14 (FGFR3-S249C) cells) can be suspended and dispensed into plates. In some embodiments, cells (e.g., DMS-114 (FGFR1-overexpressing) cells) can be suspended and dispensed into plates. In some embodiments, cells (e.g., RT-112 (FGFR3-Tacc3 fusion) cells) can be suspended and dispensed into plates. In some embodiments, to determine the effect of a compound of the present disclosure on cell proliferation, cells (e.g., SNU-16, UM-UC-14, DMS-114, and RT112 cells) can be incubated in the presence of a vehicle control (e.g., DMSO) or in the presence of a compound of the present disclosure at various concentrations, and inhibition of cell proliferation can be determined by luminescence quantitation (e.g., intracellular ATP content using CellTiterGlo) according to the manufacturer's protocol. In some embodiments, IC 50 To determine values, vehicle-treated cells were normalized as viable cells and proliferation was analyzed using software (eg, CDD Vault software (Collaborative Drug Discovery, Burlingame, CA)).

[0504] Pharmaceutical Composition In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient.

[0505] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table I. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table II.

[0506] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0507] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or extended-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. The compounds of the present disclosure can also be formulated for intravenous (bolus injection or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0508] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0509] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0510] Any suitable chelating agent can be used, examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0511] Any suitable preservative may be used, including, for example, quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0512] The aqueous vehicle may also contain a tonicity agent to adjust the tonicity (osmotic pressure), which may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0513] The aqueous vehicle also preferably contains a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of crosslinked acrylic acid with polyalkenyl ethers or divinyl glycol (Carbopols, e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0514] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifier. The pH modifier is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifiers are added to adjust the formulation to a target acceptable pH range. Therefore, depending on the formulation, it is not necessary to use both an acid and a base; the addition of either an acid or a base may be sufficient to bring the mixture into the desired pH range.

[0515] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (e.g., boric acid or a salt thereof, including disodium tetraborate), citrate buffer (e.g., citric acid or a salt thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0516] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0517] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of therapeutic oral administration, active compounds can be mixed with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is orally applied, rinsed and expectorated, or swallowed.Pharmaceutical compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0518] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0519] Compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0520] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0521] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with an inflammasome-associated condition referred to herein.

[0522] The magnitude of a therapeutic or prophylactic dose of a compound of the present disclosure will, of course, vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0523] How to use In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0524] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0525] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0526] In some aspects, the present disclosure provides methods of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0527] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0528] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0529] In some aspects, the present disclosure provides at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0530] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0531] In some aspects, the present disclosure provides at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0532] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0533] In some aspects, the present disclosure provides the use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0534] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0535] In some aspects, the present disclosure provides the use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0536] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0537] In some aspects, the present disclosure provides a use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0538] In some aspects, the present disclosure provides a use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0539] In some aspects, the present disclosure provides a use of at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0540] In some aspects, the present disclosure provides a use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0541] In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0542] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0543] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0544] In some aspects, the present disclosure provides methods of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0545] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0546] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0547] In some aspects, the present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0548] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0549] In some aspects, the present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0550] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0551] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0552] In some aspects, the disclosure provides the use of a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0553] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0554] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0555] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0556] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0557] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0558] In some aspects, the present disclosure provides the use of a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0559] In some aspects, the present disclosure provides methods of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0560] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0561] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0562] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0563] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0564] In some aspects, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0565] In some aspects, the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0566] In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0567] In some aspects, the present disclosure provides a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0568] In some aspects, the present disclosure provides a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0569] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0570] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0571] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0572] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0573] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0574] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer in a subject.

[0575] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0576] In some aspects, the present disclosure provides the use of a pharmaceutical kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0577] FGFR2 is a human gene located on chromosome 10 that encodes a protein known as FGFR2. FGFR3 is a human gene located on chromosome 4 that encodes a protein known as FGFR3. Both FGFR2 and FGFR3 are produced in several different isoforms through alternative splicing. The "b isoform" is primarily expressed in epithelial tissues, while the "c isoform" is primarily expressed in mesenchymal tissues.

[0578] FGFR2 and FGFR3 are members of the fibroblast growth factor receptor family. Fibroblast growth factor receptor family members are proteins located on the cell surface that bind to various members of the fibroblast growth factor (FGF) family of proteins. FGFR2 and FGFR3 have an extracellular ligand domain consisting of three immunoglobulin-like domains, a single transmembrane helix domain, and an intracellular tyrosine kinase domain. Upon binding of an FGF ligand to the extracellular ligand domain, the receptors dimerize, and the intracellular tyrosine kinase domains within the dimer cross-phosphorylate each other, thereby activating the kinase domain, which then binds to adaptor proteins and phosphorylates other intracellular signaling molecules. Fibroblast growth factor receptor family members are known to regulate various cellular processes, including, but not limited to, proliferation and differentiation, particularly in the context of development and tissue repair.

[0579] Overexpression of FGFR2 has been implicated in a variety of different cancers, including but not limited to gastric cancer and triple-negative breast cancer.

[0580] Overexpression of FGFR3 has been implicated in a variety of different cancers, including but not limited to lung and bladder cancer.

[0581] Mutations in the FGFR2 gene that produce mutant FGFR2 proteins have been implicated in a variety of different cancers, including but not limited to endometrial carcinoma and lung cancer.

[0582] Mutations in the FGFR3 gene that produce mutant FGFR3 proteins have been implicated in a variety of different cancers, including but not limited to bladder cancer.

[0583] FGFR2 gene fusions, which generate FGFR2 protein fusions, have been implicated in a variety of different cancers, including, but not limited to, bladder cancer and intrahepatic cholangiocarcinoma.

[0584] FGFR3 gene fusions, which generate FGFR3 protein fusions, have been implicated in a variety of different cancers, including, but not limited to, bladder cancer and glioblastoma.

[0585] In some embodiments, the subject is a mammal.

[0586] In some embodiments, the subject is a human.

[0587] In some embodiments, the subject has previously undergone at least one round of anti-cancer therapy.In some embodiments, the subject has previously undergone at least one round of anti-cancer therapy and has acquired resistance to anti-cancer therapy treatment.In some embodiments, the anti-cancer therapy can comprise the administration of at least one of futibatinib, pemigatinib, erdafitinib, infigratinib, and Debio-1347.

[0588] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the FGFR2 gene.

[0589] In some embodiments, the cancer is characterized by at least one oncogenic mutation in the FGFR3 gene.

[0590] It is understood that cancers characterized by at least one oncogenic mutation in the FGFR2 gene and / or FGFR3 gene are generally cancers associated with at least one oncogenic mutation in the FGFR2 gene and / or FGFR3 gene, and include, but are not limited to, cancers whose main oncogenic activity is thought to be driven by at least one oncogenic mutation in the FGFR2 gene and / or FGFR3 gene.

[0591] In some embodiments, the cancer is characterized by overexpression of the FGFR2 gene.

[0592] In some embodiments, the cancer is characterized by overexpression of the FGFR3 gene.

[0593] Cancers characterized by overexpression of the FGFR2 gene and / or the FGFR3 gene are generally cancers associated with overexpression of the FGFR2 gene and / or the FGFR3 gene, and it is understood that these include, but are not limited to, cancers whose main oncogenic activity is thought to be driven by overexpression of the FGFR2 gene and / or the FGFR3 gene.

[0594] In some embodiments, the cancer is characterized by at least one oncogenic variant in FGFR2.

[0595] In some embodiments, the cancer is characterized by at least one oncogenic variant in FGFR3.

[0596] It is understood that cancers characterized by at least one oncogenic variant in FGFR2 and / or FGFR3 are generally cancers associated with at least one oncogenic variant in FGFR2 and / or FGFR3, and include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by at least one oncogenic variant in FGFR2 and / or FGFR3.

[0597] In some embodiments, the cancer is characterized by overexpression of FGFR2.

[0598] In some embodiments, the cancer is characterized by overexpression of FGFR3.

[0599] Cancers characterized by overexpression of FGFR2 and / or FGFR3 are generally cancers associated with overexpression of FGFR2 and / or FGFR3, and are understood to include, but are not limited to, cancers whose primary oncogenic activity is believed to be driven by overexpression of FGFR2 and / or FGFR3.

[0600] An oncogenic variant of FGFR2 is understood to be an FGFR2 protein that contains at least one oncogenic mutation and that is produced as a result of expression of an FGFR2 gene that contains at least one oncogenic mutation.

[0601] An oncogenic variant of FGFR3 is understood to be an FGFR3 protein that contains at least one oncogenic mutation and that is produced as a result of expression of an FGFR3 gene that contains at least one oncogenic mutation.

[0602] In some embodiments, the subject has at least one oncogenic mutation in the FGFR2 gene.

[0603] In some embodiments, the subject has at least one oncogenic mutation in the FGFR3 gene.

[0604] In some embodiments, the subject has at least one tumor or cancer cell that expresses an oncogenic variant of FGFR2.

[0605] In some embodiments, the subject has at least one tumor or cancer cell that expresses an oncogenic variant of FGFR3.

[0606] In some embodiments, the subject has at least one tumor and / or cancer cell that overexpresses FGFR2.

[0607] In some embodiments, the subject has at least one tumor and / or cancer cell that overexpresses FGFR3.

[0608] As will be understood by those skilled in the art, in the context of a gene (e.g., FGFR2 and / or FGFR3), oncogenic mutations can include, but are not limited to, mutations that result in the substitution of one amino acid for another at a specific position within FGFR2 and / or FGFR3, mutations that result in the substitution of one or more amino acids for one or more amino acids between two specific positions within FGFR2 and / or FGFR3, mutations that result in the insertion of one or more amino acids between two positions within FGFR2 and / or FGFR3, mutations that result in the deletion of another amino acid between two positions within FGFR2 and / or FGFR3, and mutations that result in the fusion of FGFR2 and / or FGFR3, or a portion thereof, with another protein or portion thereof, or any combination thereof. As will be understood by those skilled in the art, oncogenic mutations in the context of a gene can include, but are not limited to, missense mutations, nonsynonymous mutations, insertions of one or more nucleotides, deletions of one or more nucleotides, inversions, and deletion-insertions. As will be appreciated by those skilled in the art, in the context of a gene (e.g., FGRF2 and / or FGFR3), the gene may have one or more of the aforementioned types of oncogenic mutations, including a combination of different types of oncogenic mutations.

[0609] As will be understood by those skilled in the art, in the context of a protein (e.g., FGFR2 and / or FGFR3), an oncogenic mutation includes, but is not limited to, a substitution of one amino acid for another at a specific position within FGFR2 and / or FGFR3, a substitution of one or more amino acids for one or more amino acids between two specific positions within FGFR2 and / or FGFR3, an insertion of one or more amino acids between two positions within FGFR2 and / or FGFR3, a deletion of another amino acid between two positions within FGFR2 and / or FGFR3, and a fusion of FGFR2 and / or FGFR3, or a portion thereof, with another protein or portion thereof, or any combination thereof. As will be understood by those skilled in the art, in the context of a protein (e.g., FGFR2 and / or FGFR3), a protein can have one or more of the aforementioned types of oncogenic mutations, including a combination of different types of oncogenic mutations.

[0610] In some embodiments, the oncogenic mutation in FGFR2 can be any of the FGFR2 mutations presented in Table 1a. In some embodiments, the oncogenic mutation in FGFR2 can be a gatekeeper mutation that confers resistance to existing inhibitors, in which case the gatekeeper mutation is V565I or V565F. [Table 3]

[0611] In some embodiments, the oncogenic mutation in FGFR3 can be any of the FGFR3 mutations presented in Table lb. In some embodiments, the oncogenic mutation in FGFR3 can be a gatekeeper mutation that confers resistance to existing inhibitors, in which case the gatekeeper mutation is V555M, V555L, or V555F. [Table 4]

[0612] In some embodiments, the oncogenic variant of FGFR2 can be any of the FGFR2 variants presented in Table 1c. [Table 5]

[0613] In some embodiments, the oncogenic variant of FGFR3 can be any of the FGFR3 variants presented in Table 1d. [Table 6]

[0614] In some embodiments, the oncogenic variant of FGFR2 may comprise a gatekeeper mutation that confers resistance to existing inhibitors, in which case the gatekeeper mutation is V565I or V565F.

[0615] In some embodiments, the oncogenic variant of FGFR3 may comprise a gatekeeper mutation that confers resistance to existing inhibitors, in which case the gatekeeper mutation is V555M, V555L, or V555F.

[0616] As used herein, the term "activating mutation" refers to any oncogenic mutation that results in at least one of: a) increased ligand binding of FGFR2 and / or FGFR3; b) ligand-independent dimerization and activation of FGFR2 and / or FGFR3; and c) increased kinase activity of FGFR2 and / or FGFR3.

[0617] In some embodiments, the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, kidney cancer, renal cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cavity cancer, pharyngeal cancer, or colorectal cancer.

[0618] In some embodiments, the cancer is adrenocortical carcinoma, urothelial carcinoma of the bladder, invasive breast carcinoma, squamous cell carcinoma of the cervix, endocervical adenocarcinoma, bile duct carcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, chromophobe cell carcinoma of the kidney, clear cell carcinoma of the kidney, papillary cell carcinoma of the kidney, acute myeloid leukemia, low-grade glioma of the brain, hepatocellular carcinoma of the liver, adenocarcinoma of the lung, squamous cell carcinoma of the lung, mesothelioma, serous cystadenocarcinoma of the ovary, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, or uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer, or gastric cancer. Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary (CUP), cancer metastasized to bone, cancer metastasized to brain, cancer metastasized to liver, cancer metastasized to lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell carcinoma, Cell sarcoma, gallbladder cancer, stomach cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, gastric fibroblastic fibrosis, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumors, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral cavity and oropharyngeal cancer, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer.Retinoblastoma, salivary gland cancer, secondary cancers, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumors, uterine cancer, including vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and gynecological cancer. Examples of cancer also include, but are not limited to, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chromocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0619] In some embodiments, the cancer is gastric cancer, triple-negative breast cancer, melanoma, hepatobiliary cancer, cancer of unknown primary origin, esophagogastric cancer, cervical cancer, head and neck cancer, CNS cancer, brain cancer, NSCLC, ovarian cancer, breast cancer, soft tissue sarcoma, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, lung cancer, bladder cancer, endometrial carcinoma, intrahepatic cholangiocarcinoma, or glioblastoma.

[0620] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0621] While not intending to be limited by this description, various options for variables are described herein, and the present disclosure is intended to encompass workable embodiments having combinations of options, the present disclosure may be construed to exclude inoperable embodiments caused by a particular combination of options.

[0622] It should be understood that compounds of the present disclosure may be depicted in neutral, cationic (e.g., carrying one or more positive charges), or anionic (e.g., carrying one or more negative charges) forms, all of which are intended to be within the scope of the present disclosure. For example, when a compound of the present disclosure is depicted in anionic form, it should be understood that such depiction also refers to various neutral, cationic, and anionic forms of the compound. As another example, when a compound of the present disclosure is depicted in anionic form, it should be understood that such depiction also refers to various salts (e.g., sodium salts) of the anionic form of the compound.

[0623] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0624] As used herein, "alkyl," "C1, C2, C3, C4, C5 or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups, and C3, C4, C5 or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, moieties having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight-chain or branched-chain alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain, C3-C6 for branched-chain), and in other embodiments, a straight-chain or branched-chain alkyl has 4 or fewer carbon atoms.

[0625] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0626] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched-chain alkenyl groups. In certain embodiments, a straight-chain or branched-chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0627] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0628] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., erynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, a straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include a C2, C3, C4, C5, or C6 alkenylene linker group.

[0629] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0630] Other optionally substituted moieties (such as, for example, optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0631] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10, or C3-C8), a saturated or partially unsaturated hydrocarbon mono- or polycyclic (e.g., fused, bridged, or spirocyclic) system. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. For polycyclic cycloalkyls, only one of the rings in the cycloalkyl need be non-aromatic.

[0632] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, and tetrahydrothiopyranyl. , 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'- isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolyl Examples of heterocyclic heterocycloalkyls include 2-azaspiro[3.4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl need be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0633] As used herein, the term "aryl" includes groups having aromatic character, including "conjugated," or polycyclic ring systems having one or more aromatic rings, and no heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, the aryl is phenyl.

[0634] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heteroaromatic rings consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O, and S(O)). p , where p=1 or 2). Note that the total number of S and O atoms in the aromatic heterocycle is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0635] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0636] In some embodiments, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may have at one or more ring positions (e.g., a ring carbon or a heteroatom such as N) a substituent such as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic acid, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl The aryl and heteroaryl groups may be substituted with aryl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylic acid, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0637] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a group selected from a specified group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents are not present in aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[0638] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the intervening atom through which it is bonded to the remainder of the compound of a given formula, then that substituent may be bonded through any atom in that formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0639] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, then that group may be optionally substituted with up to 2 R moieties, and R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0640] As used herein, the term "hydroxy" or "hydroxyl" refers to -OH or -O - The group includes a group having the formula:

[0641] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0642] The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0643] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl group having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0644] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups may be optionally substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0645] As used herein, the expressions "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, or C," and the like are used interchangeably and refer to a selection from the group consisting of all, A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof, unless otherwise indicated.

[0646] It should be understood that the present disclosure provides methods for synthesizing compounds of any of the formulas described herein. The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to those shown in the following schemes and examples.

[0647] Throughout the description, when a composition is described as having, including, or comprising particular components, it should be understood that the composition is also contemplated as consisting essentially of or consisting of the listed components. Similarly, when a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of or consists of the listed process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0648] It should be understood that the synthetic processes of the present disclosure can tolerate a wide range of functional groups and, therefore, can employ a variety of substituted starting materials. While the processes generally provide the desired final compound at or near the completion of the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0649] It will be understood that the compounds of the present disclosure can be made in a variety of ways using commercially available starting materials, compounds known in the literature, or readily made intermediates by employing standard synthetic methods and procedures that are known to those of skill in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. See, for example, but not limited to, any one or more sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001, Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and widely recognized references on organic synthesis known to those skilled in the art and are incorporated herein by reference.

[0650] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from the reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish between similar functional groups in a molecule. Lists of protecting groups, and methods for introducing and removing these protecting groups, can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

[0651] Unless otherwise specified, any reference to a method of treatment should be understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating or prophylaxis of such conditions. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models.

[0652] As used herein, the term "subject" includes human and non-human mammals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In some embodiments, the subject is a human.

[0653] As used herein, the term "subject in need thereof" refers to a subject who has a disease or is at high risk of developing a disease. A subject in need thereof may be a subject who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject who is at high risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who is more prone to developing such a disorder compared to the population as a whole). A subject in need thereof may be refractory or resistant to a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). A subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof has undergone all known effective therapies for a disease or disorder disclosed herein to no avail. In some embodiments, a subject in need thereof has undergone at least one previous therapy.

[0654] As used herein, the term "treating" or "treat" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include the treatment of a cell in vitro or in an animal model.

[0655] It will be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may prevent or may be used to prevent the associated disease, condition or disorder, or may be used to identify suitable candidates for such purposes.

[0656] As used herein, the terms "preventing," "prevent," or "protect from" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0657] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, one skilled in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure.

[0658] In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. However, it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0659] It will be appreciated that those skilled in the art can refer to general reference texts for detailed descriptions of known techniques described herein or equivalent techniques, including Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3 rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000), Colligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY, Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing. Co.,Easton,PA,18 th These texts may, of course, be referenced when making or using aspects of the present disclosure.

[0660] It will be appreciated that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0661] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound, or a salt thereof, a hydrate thereof, a solvate thereof, or an isomer thereof) in a unit dose of the composition is an effective amount and will vary according to the specific treatment involved. Those skilled in the art will recognize that routine variations in dosage may be necessary depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any required preservatives, buffers, or propellants.

[0662] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, substances, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0663] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise harmful, useful in preparing pharmaceutical compositions, and includes excipients that are applicable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more excipients.

[0664] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous use may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. pH may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0665] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many of the well-known methods currently used in chemotherapy treatment. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavities, or taken orally, or applied through the skin using a patch. The selected dose should be sufficient to provide effective treatment, but not so high as to cause unacceptable side effects. The patient's condition (e.g., a disease or disorder disclosed herein) and health status should preferably be closely monitored during treatment and for an appropriate period after treatment.

[0666] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents a specified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0667] It should be understood that for any composition, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of tumor cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be assessed by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose that is therapeutically effective in 50% of the population), and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the ratio LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0668] Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that can be taken into consideration include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, concurrent medications, reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0669] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by a generally known method, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation.Of course, the appropriate formulation depends on the selected route of administration.

[0670] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Suitable carriers for intravenous administration include physiological saline, bacteriostatic water for injection, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0671] Sterile injectable solution can be prepared by incorporating the required amount of active compound in a suitable solvent with one or a combination of the above-listed ingredients as needed, and then sterilizing by filtration.Dispersion is usually prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and other required ingredients from those listed above.For the preparation of sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which obtains powder of active ingredient and any additional desired ingredients from the solution that has been previously sterilized and filtered.

[0672] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of therapeutic oral administration, active compounds can be mixed with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is orally applied, rinsed and expectorated, or swallowed.Pharmaceutical compatible binders and / or auxiliary substances can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0673] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0674] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salve, gel, or cream, as is generally known in the art.

[0675] The active compounds can be prepared with pharmaceutically acceptable carriers that protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0676] Formulation of oral or parenteral compositions in dosage unit form is particularly advantageous for ease of administration and uniformity of administration.As used herein, dosage unit form refers to a physically discrete unit suitable as a unitary dose for a subject to be treated, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect, including the necessary pharmaceutical carrier.The specifications for the dosage unit form of the present disclosure are determined and directly depend on the inherent characteristics of the active compound and the specific therapeutic effect to be achieved.

[0677] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors that will influence the selected dosage. Generally, the dosage should be sufficient to delay, and preferably cause regression of, the symptoms of a disease or disorder disclosed herein, and preferably complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. In preferred embodiments, dosages can range from about 1 mg / kg per day to about 1000 mg / kg per day. In certain embodiments, the dose ranges from about 0.1 mg / day to about 50 g / day, about 0.1 mg / day to about 25 g / day, about 0.1 mg / day to about 10 g / day, about 0.1 mg / day to about 3 g / day, or about 0.1 mg / day to about 1 g / day, in single, divided, or continuous doses (this dose is based on the patient's weight (kg), body surface area (m), etc.). 2 ), and age (years). An effective amount of a pharmaceutical agent is an amount that produces an objectively discernible improvement as seen by a clinician or other expert observer. Improved survival and growth indicate regression. As used herein, the term "effective dosage" refers to the amount of an active compound that produces a desired biological effect in a subject or cell.

[0678] It should be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0679] It should be understood that the compounds of the present disclosure are capable of further forming salts, and therefore all of these forms are also intended to be within the scope of the claimed disclosure.

[0680] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such common non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxybenzo ... Included are salts derived from inorganic and organic acids selected from sinaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0681] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0682] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, and muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton in the parent compound is replaced with a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1 or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0683] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0684] The compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0685] Dosage regimens using the present compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the renal and hepatic function of the patient, the particular compound or salt thereof being used, etc. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, retard, or arrest the progress of the condition.

[0686] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In certain embodiments, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds will be included in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0687] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, one skilled in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure.

[0688] In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. However, it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0689] As will be understood by those skilled in the art, the FGFR2 gene is commonly referred to as one of FGFR2, fibroblast growth factor receptor 2, BEK, JWS, BBDS, CEK3, CFD1, ECT1, KGFR, TK14, TK25, BFR-1, CD332, cluster of differentiation 332, and K-SAM, and therefore, these terms are used interchangeably herein to refer to the FGFR2 gene.

[0690] As will be understood by those skilled in the art, the FGFR2 protein encoded by the FGFR2 gene is commonly referred to as one of FGFR2, fibroblast growth factor receptor 2, BEK, JWS, BBDS, CEK3, CFD1, ECT1, KGFR, TK14, TK25, BFR-1, CD332, cluster of differentiation 332, and K-SAM. Accordingly, these terms are used interchangeably herein to refer to the FGFR2 protein.

[0691] As used herein, the term FGFR2 can refer to any isoform of the FGFR2 protein, including, but not limited to, FGFR2-IIIB and FGFR2-IIIC.

[0692] As will be understood by those skilled in the art, the FGFR3 gene is commonly referred to as one of FGFR3, fibroblast growth factor receptor 3, ACH, CD333, cluster of differentiation 333, CEK2, HSFGFR3EX, and JTK4, and therefore these terms are used interchangeably herein to refer to the BRAF gene.

[0693] As will be understood by those skilled in the art, the FGFR3 protein encoded by the FGFR3 gene is commonly referred to as one of FGFR3, fibroblast growth factor receptor 3, ACH, CD333, cluster of differentiation 333, CEK2, HSFGFR3EX, and JTK4, and therefore, these terms are used interchangeably herein to refer to the FGFR3 protein.

[0694] As used herein, the term FGFR2 can refer to any isoform of the FGFR2 protein, including, but not limited to, FGFR2-IIIB and FGFR2-IIIC.

[0695] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference herein. Citation of publications and patent documents does not constitute an admission that any is pertinent prior art, nor any admission as to the contents or date. While the invention has been described by way of description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the above description and the examples set forth below are intended to be illustrative and not limiting on the scope of the claims which follow.

[0696] Exemplary Embodiments Embodiment 1. A compound of formula (I'): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to one double bond and one single bond, C(R W1 ) and when connected to two single bonds, N(R W1 ) or when connected to one double bond and one single bond, N; R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to one double bond and one single bond, C(R W2) and when connected to two single bonds, N(R W2 ) or O, or when connected to one double bond and one single bond, is N; R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, W 4 is C(R W4 ) or N, R W4 is H, halogen, cyano, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 5 is C(R W5 ) or N, R W5 is H, halogen, cyano, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 6 is connected to one double bond and one single bond, C(R W6 ) and when connected to two single bonds, N(R W6 ) or when connected to one double bond and one single bond, N; R W6 is H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 haloalkyl, or —S(═O)2—(C1-C6 alkyl); X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 3is H, halogen, cyano, NH2, -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 Aryl or 5-10 membered heteroaryl, and the above-mentioned -NH(C1-C6 alkyl), -NHC(=O)(C1-C6 haloalkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)H, -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R 3a and optionally substituted with Each R 3a are independently halogen, cyano, oxo, -OH, NH2, -NH(C1-C6 alkyl), -NHC(=O)O(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the NHC(=O)O(C1-C6 alkyl) is optionally substituted with one or more halogens; R 5 is H, halogen, cyano, or C1-C6 alkyl; R 6 is H, halogen, cyano, or C1-C6 alkyl; Y is absent, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxyl is selected from the group consisting of one or more halogen, oxo, cyano, —OH, NH2, —NH(C1-C6 alkyl)—OH, C1-C6 alkyl, C2-C6 alkenyl, —(C1-C6 alkyl)(C6-C 10 C1-C6 alkoxy optionally substituted with aryl, or C3-C 12 optionally substituted with cycloalkyl; Z is absent, H, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 aryl or 5-10 membered heteroaryl, and the C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C6-C 10 An aryl or a 5- to 10-membered heteroaryl may be one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, ═NR Za , NH2, NHR Za , NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(C1-C6 alkyl), -S(=O)(=NR Za )-(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -S(=O)2-(C2-C6 alkenyl), -C(=O)(3-12 membered heterocycloalkyl), -C(=O)NH(C1-C6 alkyl), -C(=O)NR Za, -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), -C(=O)-(C1-C6 alkoxyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, and is selected from the group consisting of NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl, a 3- to 12-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl may be one or more R Za and optionally substituted with Each R Za are independently H, oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 Cycloalkyl, or 3-12-membered heterocycloalkyl, and the above-mentioned NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C 12 A cycloalkyl or 3- to 12-membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zbare independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0697] Embodiment 2. A compound of formula (I): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: each [ka] independently represent a single bond or a double bond; n is 0 or 1, W 1 is connected to two single bonds, C(R W1 ) or N(R W1 ) or when connected to one double bond and one single bond, is C or N, R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to two single bonds, C(R W2 ) or N(R W2 ) or when connected to one double bond and one single bond, is C or N, R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2is H or C1-C6 alkyl, X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl, R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2 is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is absent or is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is H, C3-C8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Zaare independently oxo, halogen, cyano, -OH, NH, NH(C-C alkyl), N(C-C alkyl), -S(=O)-(C-C alkyl), -C(=O)-(C-C alkyl), -C(=O)-(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxyl, C-C cycloalkyl, or a 3- to 8-membered heterocyclic group. cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb are independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0698] Embodiment 3. each [ka] each independently represents a single bond or a double bond; n is 0 or 1, W 1 is connected to two single bonds, C(R W1 ) or N(R W1 ) or when connected to one double bond and one single bond, is C or N, R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2is connected to two single bonds, C(R W2 ) or N(R W2 ) or when connected to one double bond and one single bond, is C or N, R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl; X 3 is N, O, or C(R X3 ) and R X3 is H or C1-C6 alkyl; R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2 is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is absent or is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Z and optionally substituted with Each R Zare independently oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered hetero cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Za are independently oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered hetero cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zbis independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0699] Embodiment 4. each [ka] each independently represents a single bond or a double bond; n is 0 or 1, W 1 is connected to two single bonds, C(R W1 ) or N(R W1 ) or when connected to one double bond and one single bond, is C or N, R W1 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 2 is connected to two single bonds, C(R W2 ) or N(R W2 ) or when connected to one double bond and one single bond, is C or N, R W2 is H, C1-C6 alkyl, or —S(═O)2-(C1-C6 alkyl), W 3 is C or N, X 1 is C or N, X 2 is N, O, or C(R X2 ) and R X2 is H or C1-C6 alkyl; X 3 is N, O, or C(R X3 ) and R X3is H or C1-C6 alkyl; R 1 is H, halogen, cyano, or C1-C6 alkyl; R 2 is H, halogen, cyano, or C1-C6 alkyl; R 3 is H, halogen, cyano, or C1-C6 alkyl; R 4 is H, halogen, cyano, or C1-C6 alkyl; Y is C1-C6 alkyl optionally substituted with one or more oxo or -OH; Z is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Z and optionally substituted with Each R Z are independently oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered hetero cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Za and optionally substituted with Each R Zaare independently oxo, halogen, cyano, -OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered hetero cycloalkyl, and the NH(C1-C6 alkyl), N(C1-C6 alkyl), -S(=O)2-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)-(C2-C6 alkenyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C3-C8 cycloalkyl, or 3-8 membered heterocycloalkyl may be one or more R Zb and optionally substituted with Each R Zb is independently oxo, halogen, cyano, —OH, NH, NH(C-C alkyl), N(C-C alkyl), —S(═O)—(C-C alkyl), —C(═O)—(C-C alkyl), —C(═O)—(C-C alkenyl), C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C alkoxyl.

[0700] Embodiment 5. [ka] but, [ka] The compound of any one of the preceding embodiments, wherein

[0701] Embodiment 6. [ka] but, [ka] The compound of any one of the preceding embodiments, wherein

[0702] Embodiment 7. [ka] but, [ka] The compound of any one of the preceding embodiments, wherein

[0703] Embodiment 8. [ka] but, [ka] The compound of any one of the preceding embodiments, wherein

[0704] Embodiment 9. [ka] but, [ka] The compound of any one of the preceding embodiments, wherein

[0705] Embodiment 10. [ka] but, [ka] The compound of any one of the preceding embodiments, wherein

[0706] Embodiment 11.R 1 is H.

[0707] Embodiment 12.R1 The compound of any one of the preceding embodiments, wherein is halogen, cyano, or C1-C6 alkyl.

[0708] Embodiment 13.R 1 The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl.

[0709] Embodiment 14.R 1

[0023] The compound of any one of the preceding embodiments, wherein is CH3.

[0710] Embodiment 15.R 2 is H.

[0711] Embodiment 16.R 2 The compound of any one of the preceding embodiments, wherein is halogen, cyano, or C1-C6 alkyl.

[0712] Embodiment 17.R 3 is H.

[0713] Embodiment 18.R 3 The compound of any one of the preceding embodiments, wherein is halogen, cyano, or C1-C6 alkyl.

[0714] Embodiment 19.R 3 The compound of any one of the preceding embodiments, wherein is halogen.

[0715] Embodiment 20.R 3 The compound of any one of the preceding embodiments, wherein is Cl.

[0716] Embodiment 21.R 3 The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl.

[0717] Embodiment 22.R 3

[0023] The compound of any one of the preceding embodiments, wherein is CH3.

[0718] Embodiment 23.R 4 is H.

[0719] Embodiment 24.R 4 The compound of any one of the preceding embodiments, wherein is halogen, cyano, or C1-C6 alkyl.

[0720] Embodiment 25.R 4 The compound of any one of the preceding embodiments, wherein is halogen.

[0721] Embodiment 26.R 4 The compound of any one of the preceding embodiments, wherein is Cl.

[0722] Embodiment 27.R 4 The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl.

[0723] Embodiment 28.R 4

[0023] The compound of any one of the preceding embodiments, wherein is CH3.

[0724] Embodiment 29. A compound of any one of the preceding embodiments, wherein Y is absent.

[0725] Embodiment 30. A compound according to any one of the preceding embodiments wherein Y is C1-C6 alkyl optionally substituted with one or more oxo or -OH.

[0726] Embodiment 31. A compound according to any one of the preceding embodiments, wherein Y is C1-C6 alkyl.

[0727] Embodiment 32. A compound according to any one of the preceding embodiments, wherein Y is -CH2-.

[0728] Embodiment 33. A compound according to any one of the preceding embodiments wherein Y is C1-C6 alkyl substituted with one or more oxo or -OH.

[0729] Embodiment 34. A compound of any one of the preceding embodiments wherein Z is H.

[0730] Embodiment 35. Z is C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein said C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Z The compound of any one of the preceding embodiments, optionally substituted with

[0731] Embodiment 36. Z is azetidinyl or oxetanyl, wherein said azetidinyl or oxetanyl is selected from the group consisting of one or more R Z The compound of any one of the preceding embodiments, optionally substituted with

[0732] Embodiment 37. A compound of any one of the preceding embodiments wherein Z is azetidinyl or oxetanyl.

[0733] Embodiment 38. Z is pyrrolidinyl or tetrahydrofuranyl, wherein said pyrrolidinyl or tetrahydrofuranyl is selected from the group consisting of one or more R Z The compound of any one of the preceding embodiments, optionally substituted with

[0734] Embodiment 39. A compound of any one of the preceding embodiments wherein Z is pyrrolidinyl or tetrahydrofuranyl.

[0735] Embodiment 40. Z is piperidinyl or tetrahydropyranyl, wherein said piperidinyl or tetrahydropyranyl is selected from the group consisting of one or more R Z The compound of any one of the preceding embodiments, optionally substituted with

[0736] Embodiment 41. A compound according to any one of the preceding embodiments, wherein Z is piperidinyl or tetrahydropyranyl.

[0737] Embodiment 42. At least one R Z The compound of any one of the preceding embodiments, wherein is oxo, halogen, cyano, —OH.

[0738] Embodiment 43. At least one R Z is NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Za The compound of any one of the preceding embodiments, optionally substituted with

[0739] Embodiment 44. At least one R Z but one or more R Za The compound of any one of the preceding embodiments, wherein S(=O)2-(C1-C6 alkyl) optionally substituted with

[0740] Embodiment 45. At least one R Z is -C(=O)-(C1-C6 alkyl) or -C(=O)-(C2-C6 alkenyl), and the -C(=O)-(C1-C6 alkyl) or -C(=O)-(C2-C6 alkenyl) is selected from the group consisting of one or more R Za The compound of any one of the preceding embodiments, optionally substituted with

[0741] Embodiment 46. At least one R Z The compound of any one of the preceding embodiments, wherein is —C(═O)—CH═CH2.

[0742] Embodiment 47. At least one R Z is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl is selected from the group consisting of one or more RZa The compound of any one of the preceding embodiments, optionally substituted with

[0743] Embodiment 48. At least one R Z but one or more R Za The compound of any one of the preceding embodiments, wherein R is C1-C6 alkyl optionally substituted with

[0744] Embodiment 49. At least one R Z is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Za The compound of any one of the preceding embodiments, optionally substituted with

[0745] Embodiment 50. At least one R Za The compound of any one of the preceding embodiments, wherein is oxo, halogen, cyano, —OH.

[0746] Embodiment 51. At least one R Za is NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2, and the NH(C1-C6 alkyl) or N(C1-C6 alkyl)2 is selected from one or more R Zb The compound of any one of the preceding embodiments, optionally substituted with

[0747] Embodiment 52. At least one R Za but one or more R Zb The compound of any one of the preceding embodiments, wherein S(=O)2-(C1-C6 alkyl) optionally substituted with

[0748] Embodiment 53. At least one R Za is -C(=O)-(C1-C6 alkyl) or -C(=O)-(C2-C6 alkenyl), and the -C(=O)-(C1-C6 alkyl) or -C(=O)-(C2-C6 alkenyl) is selected from the group consisting of one or more R ZbThe compound of any one of the preceding embodiments, optionally substituted with

[0749] Embodiment 54. At least one R Za The compound of any one of the preceding embodiments, wherein is —C(═O)—CH═CH2.

[0750] Embodiment 55. At least one R Za is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl, and the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl is selected from the group consisting of one or more R Zb The compound of any one of the preceding embodiments, optionally substituted with

[0751] Embodiment 56. At least one R Za is a C3-C8 cycloalkyl or a 3- to 8-membered heterocycloalkyl, and the C3-C8 cycloalkyl or the 3- to 8-membered heterocycloalkyl is selected from the group consisting of one or more R Zb The compound of any one of the preceding embodiments, optionally substituted with

[0752] Embodiment 57. At least one R Zb The compound of any one of the preceding embodiments, wherein is oxo, halogen, cyano, —OH.

[0753] Embodiment 58. At least one R Zb The compound of any one of the preceding embodiments, wherein is NH2, NH(C1-C6 alkyl), or N(C1-C6 alkyl)2.

[0754] Embodiment 59. At least one R Zb The compound of any one of the preceding embodiments, wherein is S(=O)2-(C1-C6 alkyl).

[0755] Embodiment 60. At least one R ZbThe compound of any one of the preceding embodiments, wherein is —C(═O)—(C1-C6 alkyl) or —C(═O)—(C2-C6 alkenyl).

[0756] Embodiment 61. At least one R Zb The compound of any one of the preceding embodiments, wherein is —C(═O)—CH═CH2.

[0757] Embodiment 62. At least one R Zb The compound of any one of the preceding embodiments, wherein is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxyl.

[0758] Embodiment 63. Formula (Ia), (Ib), (Ic), or (Id): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0759] Embodiment 64. A compound of formula (II): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0760] Embodiment 65. Formula (II-a), (II-b), (II-c), or (II-d): [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0761] Embodiment 66. A compound according to any one of the preceding embodiments, selected from the compounds set forth in Table I and Table II, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0762] Embodiment 67. An isotopic derivative of a compound according to any one of the preceding embodiments.

[0763] Embodiment 68. A method for preparing a compound according to any one of the preceding embodiments.

[0764] Embodiment 69. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments and one or more pharmaceutically acceptable carriers or excipients.

[0765] Embodiment 70. A method of treating or preventing cancer in a subject, the method comprising administering to the subject a compound of any one of the preceding embodiments.

[0766] Embodiment 71. A compound of any one of the preceding embodiments for treating or preventing cancer in a subject.

[0767] Embodiment 72. Use of a compound of any one of the preceding embodiments in the manufacture of a medicament for treating or preventing cancer in a subject.

[0768] Embodiment 73. Use of a compound according to any one of the preceding embodiments for treating or preventing cancer in a subject.

[0769] Embodiment 74. The method, compound, or use of any one of embodiments 70 to 73, wherein the subject is a human.

[0770] Embodiment 75. The method, compound, or use of any one of embodiments 70 to 74, wherein the subject has previously received at least one round of anti-cancer therapy.

[0771] Embodiment 76. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by at least one oncogenic mutation in the FGFR2 gene.

[0772] Embodiment 77. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by at least one oncogenic mutation in the FGFR3 gene.

[0773] Embodiment 78. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by overexpression of the FGFR2 gene.

[0774] Embodiment 79. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by overexpression of the FGFR3 gene.

[0775] Embodiment 80. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by at least one oncogenic variant of FGFR2.

[0776] Embodiment 81. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by at least one oncogenic variant of FGFR3.

[0777] Embodiment 82. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by overexpression of FGFR2.

[0778] Embodiment 83. The method, compound, or use of any one of embodiments 70 to 75, wherein the cancer is characterized by overexpression of FGFR3.

[0779] Embodiment 84. The method, compound, or use of any one of embodiments 70 to 83, wherein the cancer is carcinoma, lymphoma, blastoma, sarcoma, leukemia, brain cancer, breast cancer, blood cancer, bone cancer, lung cancer, skin cancer, liver cancer, ovarian cancer, bladder cancer, kidney cancer, renal cancer, gastric cancer, thyroid cancer, pancreatic cancer, esophageal cancer, prostate cancer, cervical cancer, uterine cancer, stomach cancer, soft tissue cancer, laryngeal cancer, small intestine cancer, testicular cancer, anal cancer, vulvar cancer, joint cancer, oral cavity cancer, pharyngeal cancer, or colorectal cancer.

[0780] Embodiment 85. The method of any one of embodiments 70 to 83, wherein the cancer is adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, bile duct carcinoma, colon adenocarcinoma, lymphoid tumor diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney chromophobe cell carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, acute myeloid leukemia, brain low-grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, mesothelioma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pheochromocytoma, paraganglioma, prostate adenocarcinoma, rectal adenocarcinoma, sarcoma, skin cutaneous melanoma, gastric adenocarcinoma, testicular germ cell tumor, thyroid carcinoma, thymoma, uterine carcinosarcoma, uveal melanoma. Other examples include breast cancer, lung cancer, lymphoma, melanoma, liver cancer, colorectal cancer, ovarian cancer, bladder cancer, renal cancer, or gastric cancer. Further examples of cancer include neuroendocrine cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, thyroid cancer, endometrial cancer, biliary tract cancer, esophageal cancer, anal cancer, salivary cancer, vulvar cancer, cervical cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal tumors, anal cancer, bile duct cancer, bladder cancer, bone cancer, intestinal cancer, brain tumor, breast cancer, cancer of unknown primary (CUP), cancer metastasized to bone, cancer metastasized to brain, cancer metastasized to liver, cancer metastasized to lung, carcinoid, cervical cancer, childhood cancer, chronic lymphocytic leukemia (CLL), chromic myeloid leukemia (CML), colorectal cancer, ear cancer, endometrial cancer, eye cancer, follicular dendritic cell carcinoma, Cell sarcoma, gallbladder cancer, stomach cancer, gastroesophageal junction cancer, germ cell tumors, gestational trophoblastic disease (GIT), hairy cell leukemia, head and neck cancer, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leukemia, gastric fibroblastic fibrosis, liver cancer, lung cancer, lymphoma, malignant neurilemmoma, mediastinal germ cell tumors, melanoma skin cancer, male cancer, Merkel cell skin cancer, mesothelioma, molar pregnancy, oral cavity and oropharyngeal cancer, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, non-Hodgkin's lymphoma (NHL), esophageal cancer, ovarian cancer, pancreatic cancer, penile cancer, persistent trophoblastic disease and choriocarcinoma, pheochromocytoma, prostate cancer, pseudomyxoma peritonei, rectal cancer.Retinoblastoma, salivary gland cancer, secondary cancers, signet cell cancer, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, T-cell childhood non-Hodgkin's lymphoma (NHL), testicular cancer, thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, adrenal tumors, uterine cancer, including vaginal cancer, vulvar cancer, Wilms' tumor, uterine cancer, and gynecological cancer. Examples of cancer also include, but are not limited to, hematological malignancies, lymphoma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, chromocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, myelodysplastic syndrome, myelofibrosis, biliary tract cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, thyroid carcinoma, renal cell carcinoma, pancreatic cancer, bladder cancer, skin cancer, malignant melanoma, Merkel cell carcinoma, uveal melanoma, or glioblastoma multiforme.

[0781] Embodiment 86. The method, compound, or use of any one of embodiments 70 to 83, wherein the cancer is gastric cancer, triple-negative breast cancer, melanoma, hepatobiliary cancer, cancer of unknown primary origin, esophagogastric cancer, cervical cancer, head and neck cancer, CNS cancer, brain cancer, NSCLC, ovarian cancer, breast cancer, soft tissue sarcoma, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, lung cancer, bladder cancer, endometrial carcinoma, intrahepatic cholangiocarcinoma, or glioblastoma. [Example]

[0782] For illustrative purposes, salts of compounds of formula (I') and (I) are synthesized and tested in the Examples. It is understood that neutral compounds of formula (I') and (I) can be similarly synthesized and tested using the exemplary procedures described in the Examples. It is further understood that salts (e.g., sodium salts) of compounds of formula (I') and (I) can be converted to the corresponding neutral compounds using techniques routine in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).

[0783] The compounds of formula (I') and (I) can be prepared using the methods detailed herein. Those skilled in the art can envision alternative synthetic routes using a variety of starting materials and reagents to prepare the disclosed compounds of formula (I') and (I) and make further modifications. For illustrative purposes, some salts of the compounds of formula (I') and (I) are synthesized and tested in the Examples. It is understood that neutral compounds of formula (I') and (I) can be similarly synthesized and tested using the exemplary procedures described in the Examples. Furthermore, it is understood that salts (e.g., hydrochloride salts) of the compounds of formula (I') and (I) can be converted to the corresponding neutral compounds using routine techniques in the art (e.g., pH adjustment and, optionally, extraction (e.g., into an aqueous phase)).

[0784] Abbreviation [Table 7]

[0785] Synthesis of intermediates Intermediates 1 and 34: 8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinoxaline and tert-butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] Step 1. tert-Butyl 4-(tosyloxy)piperidine-1-carboxylate

[0786] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.48 mmol) in dichloromethane (10 mL) was added triethylamine (754 mg, 7.45 mmol) and p-toluenesulfonyl chloride (947 mg, 4.97 mmol). The mixture was stirred at 25 °C for 16 hours. Upon completion, the mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with 1 M hydrochloric acid (10 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to afford tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (600 mg, 1.69 mmol, 67% yield) as a white solid.

[0787] Step 2. tert-Butyl 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate

[0788] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g, 1.97 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.29 g, 3.94 mmol) and tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (841 mg, 2.37 mmol). The mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (2 g, crude) as a yellow oil. 1H NMR (400 MHz, CD3OD) δ 9.29(d,J=2.8Hz,1H),8.76(s,1H),8.48(s,1H),7.74(dd,J=7.2,8.8Hz,1H),7. 56(d,J=8.0Hz,1H),7.48(dd,J=9.2,11.2Hz,1H),7.38(dd,J=2.0,13.8Hz,1H), 7.23-7.16(m,1H),5.79-5.64(m,2H),4.38(d,J=13.2Hz,2H),3.80-3.56(m,4H) ,2.29-2.08(m,4H),1.62-1.54(m,9H),1.08-0.81(m,2H),0.13-0.08(m,9H);m / z ES+[M+H] + 690.4.

[0789] Step 3. 2-[[6-[5-chloro-3-[1-(4-piperidyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0790] To a solution of tert-butyl 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate (2 g, 2.90 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC (mobile phase: [water (0.225% formic acid)-acetonitrile]; (B%: 50%-55%, 10 min) to give 2-[[6-[5-chloro-3-[1-(4-piperidyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (700 mg, 1.19 mmol, 41%) as a yellow solid. 1H NMR(400MHz,CD3OD):δ=9.28(s,1H),8.73(s,1H),8.46(s,1H),8.08-7.93(m,1H), 7.77-7.70(m,1H),7.54-7.43(m,1H),7.40-7.38(m,1H),7.32-7.08(m,1H),5.82-5 .59(m,2H),4.62-4.45(m,1H),3.83-3.60(m,2H),3.40-3.17(m,2H),2.99-2.86(m ,2H),2.77 (d,J=6.4Hz,3H),2.37-2.26(m,2H),1.09-0.83(m,2H),0.08(s,9H); ES+[M+H] + 590.1.

[0791] Intermediate 2: 2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline [ka] Step 1. tert-Butyl 3-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

[0792] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2 g, 3.94 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (1.67 g, 5.92 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.09 g, 7.89 mmol). The mixture was stirred at 60 °C for 32 hours. The reaction mixture was quenched at 20 °C by the addition of water (200 mL), then diluted with ethyl acetate (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layer was washed with water (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (2.70 g, 3.67 mmol, 93%) as a yellow solid. m / z ES+ [M+H] + 662.4.

[0793] Step 2. 2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

[0794] A solution of tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (2.5 g, 3.77 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (20 mL) was stirred for 16 hours at 25° C. The reaction mixture was quenched with saturated sodium bicarbonate (50 mL) at 25° C., then diluted with dichloromethane (50 mL) and extracted with dichloromethane (50 mL×3). The combined organic layers were washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (2.0 g, 2.49 mmol, 66%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=9.48-9.37(m,1H),9.27-9.01(m,1H),8.86(s,1H),8.60(s,1H),8.07(d,J=9.2Hz,1H),7.84(d,J=9.2Hz,1H),7.56-7.48(m m / z ES+[M+H] + 562.4.

[0795] Intermediate 3: 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane 1,1-dioxide [ka] Step 1. Methyl 2-(cyanomethyl)acrylate

[0796] To a solution of methyl 2-(bromomethyl)acrylate (23.0 g, 128 mmol), trimethylsilylformonitrile (12.7 g, 128 mmol) in acetonitrile (500 mL), tetrabutylammonium fluoride (1 M in THF, 128.48 mL) was added dropwise at 25 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1) to give methyl 2-(cyanomethyl)acrylate (13.0 g, 103 mmol, 80%) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 6.40(d,J=0.8Hz,1H),6.01(s,1H),3.75(d,J=0.8Hz,3H),3.35(s,2H).

[0797] Step 2. Methyl 3-(benzylthio)-2-(cyanomethyl)propanoate

[0798] To a solution of methyl 2-(cyanomethyl)acrylate (6.50 g, 51.9 mmol) in tetrahydrofuran (80 mL) were added triethylamine (15.7 g, 155 mmol) and phenylmethanethiol (7.74 g, 62.3 mmol), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 30:1 to 15:1) to give methyl 3-(benzylthio)-2-(cyanomethyl)propanoate (22.0 g, 88.2 mmol, 85%) as a colorless oil.

[0799] Step 3. 4-Amino-2((benzylthio)methyl)butan-1-ol

[0800] To a solution of methyl 3-(benzylthio)-2-(cyanomethyl)propanoate (10.0 g, 40.1 mmol) in tetrahydrofuran (200 mL) was carefully added lithium aluminum hydride (4.57 g, 120 mmol) in small portions at 0° C. The mixture was stirred at 25° C. for 1 hour. The mixture was carefully quenched with sodium sulfate decahydrate (10 g) and water (5 mL). The resulting precipitate was filtered. The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-amino-2-((benzylthio)methyl)butan-1-ol (9 g, crude product) as a yellow oil.

[0801] Step 4. 4-(benzylthio)-3-(((tert-butyldiphenylsilyl)oxy)methyl)butan-1-amine

[0802] A solution of 4-amino-2-((benzylthio)methyl)butan-1-ol (7 g, 31.0 mmol), tert-butylchlorodimethylsilane (8.54 g, 31.0 mmol), and imidazole (3.17 g, 46.5 mmol) in dichloromethane (50 mL) was stirred at 25° C. for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% formic acid) to give 4-(benzylthio)-3-(((tert-butyldiphenylsilyl)oxy)methyl)butan-1-amine (6.60 g, 14.2 mmol, 45%) as a yellow oil. m / z ES+ [M+H] + 464.2.

[0803] Step 5. 4-Amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)butane-1-sulfonyl chloride

[0804] To a solution of 4-(benzylthio)-3-(((tert-butyldiphenylsilyl)oxy)methyl)butan-1-amine (3 g, 6.47 mmol) in acetic acid (30 mL) and water (9 mL) was added N-chlorosuccinimide (2.59 g, 19.4 mmol). The reaction was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give 4-amino-2-(((tert-butyldiphenylsilyl)oxy)methyl)butane-1-sulfonyl chloride (2.80 g, crude) as a yellow oil.

[0805] Step 6. Methyl 3-(benzylthio)-2-(cyanomethyl)propanoate

[0806] A solution of 4-amino-2-[[tert-butyl(diphenyl)silyl]oxymethyl]butane-1-sulfonyl chloride (2.8 g, 6.36 mmol) and triethylamine (1.93 g, 19.0 mmol) in dichloromethane (30 mL) was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2-thiazinane 1,1-dioxide (1 g, 2.48 mmol, 38%) as a white solid. 1 H NMR(400MHz,CDCl3) δ 7.64(d,J=7.2Hz,4H),7.56-7.36(m,7H),3.73-3.26(m,4H),2.82(t,J=12.8Hz,1H),2.52(s,1H),1.55-1.38(m,2H),1.13-1.04(m,9H).

[0807] Intermediates 4 and 5: 3-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-one and 3-(4-(8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-one [ka] Step 1. 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

[0808] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (830 mg, 1.65 mmol) and 2-bromo-5,8-dioxaspiro[3.4]octane (350 mg, 1.80 mmol) in N,N-dimethylformamide (9 mL) was added potassium carbonate (680 mg, 4.90 mmol) and potassium iodide (27.0 mg, 165 mmol). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:1 to 10:1) to give 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (680 mg, 1.05 mmol, 64%) as a yellow solid. m / z ES+ [M+H] +619.1.

[0809] Step 2. 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone

[0810] To a solution of 2-[[6-[5-chloro-3-[1-(5,8-dioxaspiro[3.4]octan-2-yl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (680 mg, 1.10 mmol) in dichloromethane (6.8 mL) and water (0.5 mL) was added formic acid (8.30 g, 180 mmol). The mixture was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure and then diluted with water (20 mL). The mixture was adjusted to pH 8-9 with saturated sodium bicarbonate (30 mL) and then extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (550 mg, crude) as a white solid. m / z ES+ [M+H] + 575.3.

[0811] Step 3. 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone

[0812] A solution of 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (350 mg, 0.61 mmol) in trifluoroacetic acid (3.5 mL) was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water (30 mL). The mixture was adjusted to pH 9 with saturated sodium carbonate solution and then extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-[4-[8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxalin-2-yl]pyrazol-1-yl]cyclobutanone (300 mg, crude product) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ=9.33(s,1H),8.95(s,1H),8.45(s,1H),7.96(d,J=9.2Hz,1H),7.52(d,J=8.8Hz,1H),7.33(d,J=9.2Hz,1H ),7.23(d,J=2.0Hz,1H),6.96(dd,J=2.4,8.8Hz,1H),5.41-5.31(m,1H),3.70-3.64(m,4H),2.50(s,3H);m / z ES+[M+H] + 445.0.

[0813] Intermediate 6: 2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-8-chloro-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline [ka] Step 1. tert-Butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate

[0814] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g, 1.97 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (1.29 g, 3.94 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (614 mg, 2.17 mmol). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 40 mm x 15 μm, mobile phase: [water (0.1% TFA)-acetonitrile], (B%: 35% to 65%, 11 min) to give tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (800 mg, 1.21 mmol, 61%) as a white solid. m / z ES+ [M+1] + 662.4.

[0815] Step 2. 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline

[0816] A mixture of tert-butyl 3-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]azetidine-1-carboxylate (790 mg, 1.19 mmol) in trifluoroacetic acid (3 mL) was stirred for 6 hours at 25° C. The reaction mixture was concentrated under reduced pressure to give 2-[1-(azetidin-3-yl)pyrazol-4-yl]-8-chloro-7-[(2-methyl-3H-benzimidazol-5-yl)oxy]quinoxaline (500 mg, crude product, TFA salt) as a yellow solid. 1H NMR(400MHz,DMSO-d6) δ=9.37(s,1H),9.26(d,J=6.4Hz,1H),8.86(s,1H),8.59(s,1H),8.02(d,J=9.2Hz,1H),7.72-7.63(m,1H),7.42( m / z ES+[M+1] + 432.2.

[0817] Intermediate 7: tert-Butyl N-tert-butoxycarbonyl-N-(3,5-difluoro-2-nitro-phenyl)carbamate [ka] Step 1. tert-Butyl N-tert-butoxycarbonyl-N-(3,5-difluoro-2-nitro-phenyl)carbamate

[0818] To a solution of 3,5-difluoro-2-nitro-aniline (500 mg, 2.87 mmol) in dichloromethane (8 mL), 4-dimethylaminopyridine (35.1 mg, 287 μmol), di-tert-butyl dicarbonate (1.25 g, 5.74 mmol), and triethylamine (872 mg, 8.62 mmol) were added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give tert-butyl N-tert-butoxycarbonyl-N-(3,5-difluoro-2-nitro-phenyl)carbamate (800 mg, 1.34 mmol, 74%) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 7.35-6.98(m,1H),6.94-6.82(m,1H),1.44(s,18H).

[0819] Intermediate 8: (3,3-Difluorocyclobutyl)methyl methanesulfonate [ka] Step 1. (3,3-Difluorocyclobutyl)methyl methanesulfonate

[0820] To a solution of (3,3-difluorocyclobutyl)methanol (5 g, 41.0 mmol) and triethylamine (10.4 g, 102 mmol) in dichloromethane (60 mL) was added methanesulfonyl chloride (7.04 g, 61.4 mmol, 4.75 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with water (15 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3,3-difluorocyclobutyl)methyl methanesulfonate (9 g, crude product) as a yellow oil. 1 H NMR(400MHz,CDCl3) δ 4.25(d,J=6.4Hz,2H),3.03(d,J=1.2Hz,3H),2.79-2.65(m,2H),2.63-2.50(m,1H),2.49-2.32(m,2H).

[0821] Intermediates 9, 10 and 11: 7-Bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline and 3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-ol and 5-chloro-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-ol [ka] Step 1. 7-Bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline

[0822] To a mixture of 7-bromo-2-chloroquinoxaline (3 g, 12.3 μmol) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.61 g, 13.0 μmol) in dioxane (30 mL) and water (6 mL) was added potassium acetate (3.63 g, 37.0 μmol) and cyclopenta-2,4-dien-1-yl(diphenyl)phosphalene; dichloropalladium; and iron(II) (902 mg, 1.23 μmol). The mixture was stirred under nitrogen at 60° C. for 12 hours. Upon completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (125 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=30:1 to 0:1) to give 7-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (2.80 g, crude product) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 9.06(s,1H),8.41(s,1H),8.29-8.20(m,2H),7.92(d,J=8.8Hz,1H),7.76(dd,J=2.0,8.8Hz,1H),5.54-5. 45(m,1H),4.21-4.08(m,1H),3.83-3.72(m,1H),2.23-2.15(m,2H),2.12-2.06(m,1H),1.76-1.66(m,3H).

[0823] Step 2. 7-Bromo-2-(1H-pyrazol-4-yl)quinoxaline

[0824] To a solution of 7-bromo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline (5.20 g, 14.5 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (20 mL), and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (5 g, crude product) as a black solid. m / z ES+ [M+H] + 274.7.

[0825] Step 3. 7-Bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline

[0826] To a solution of 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (2.30 g, 8.36 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (2.31 g, 16.7 mmol) and (3,3-difluorocyclobutyl)methyl methanesulfonate (1.67 g, 8.36 mmol), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give a residue. The residue was triturated with petroleum ether / ethyl acetate (20:1, 40 mL) at 20° C. for 30 min to give 7-bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxaline (800 mg, 2.11 mmol, 12%) as a yellow solid. 1H NMR(400MHz,DMSO-d6) δ 9.43-9.31(m,1H),8.73(s,1H),8.34(s,1H),8.20(d,J=2.0Hz,1H),7.99(d,J=8.8Hz,1H ),7.88(dd,J=2.0,8.8Hz,1H),4.37(d,J=6.0Hz,2H),3.30(s,1H),2.77-2.57(m,4H);m / z ES+[M+H] + 378.8.

[0827] Step 4. 3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-ol

[0828] A mixture of 7-bromo-2-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxaline (600 mg, 1.58 mmol), tris(dibenzylideneacetone)dipalladium (145 mg, 158 µmol), ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (67.2 mg, 158 µmol), and potassium hydroxide (888 mg, 15.8 mmol) in dioxane (10 mL) and water (2 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 100° C. for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate=5 / 1 to 1 / 1) to give 3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-ol (400 mg, 1.26 mmol, 68%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=10.69-10.25(m,1H),9.05(s,1H),8.66(s,1H),8.28(s,1H),7.86(d,J=9.2Hz,1H),7.28(dd,J= m / z ES+[M+H] + 317.1.

[0829] Step 5. 5-Chloro-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-ol

[0830] To a solution of 3-[1-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-ol (400 mg, 1.26 mmol) in chloroform (5 mL) was added N-chlorosuccinimide (338 mg, 2.53 mmol), nickel chloride (164 mg, 1.26 mmol), and triethylamine (128 mg, 1.26 mmol). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 5-chloro-3-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)quinoxalin-6-ol (500 mg, 1.43 mmol, 95%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=9.14(s,1H),8.69(s,1H),8.32(s,1H),7.86(d,J=9.2Hz,1H),7.48(d, J=9.2Hz,1H),4.37(d,J=6.0Hz,2H),3.16(s,1H),2.77-2.59(m,4H);m / z ES+[M+H] + 351.0.

[0831] Intermediate 12: tert-Butyl N-tert-butoxycarbonyl-N-(5-fluoro-2-nitrophenyl)carbamate [ka] Step 1. tert-Butyl N-tert-butoxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate

[0832] To a solution of 5-fluoro-2-nitro-aniline (10 g, 64.1 μmol) in dichloromethane (100 mL) was added di-tert-butyl dicarbonate (28.0 g, 128 μmol), triethylamine (19.5 g, 192 μmol), and N,N-dimethylpyridin-4-amine (783 mg, 6.41 μmol). The mixture was stirred at 20° C. for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 8 / 1) to give tert-butyl N-tert-butoxycarbonyl-N-(5-fluoro-2-nitro-phenyl)carbamate (20 g, 56.1 μmol, 88%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ=8.14(dd,J=5.6,9.2Hz,1H),7.23-7.14(m,1H),7.05(dd,J=2.8,8.4Hz,1H),1.40(s,18H).

[0833] Intermediate 13: 2-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate [ka] Step 1. 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanol

[0834] To a mixture of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2 g, 3.94 mmol) and 2-bromoethanol (1.48 g, 11.83 mmol, 840 μL) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.64 g, 11.83 mmol). The mixture was then heated to 80° C. and stirred for 16 hours. Upon completion, the reaction mixture was quenched with water (150 mL) at 20° C. and then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:1 to 20:1) to give 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanol (2.5 g, 3.86 mmol, 98%) as a yellow oil. m / z ES+ [M+H] + 551.4.

[0835] Step 2. 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate

[0836] To a mixture of 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethanol (2.5 g, 4.54 mmol) in dichloromethane (30 mL) was added triethylamine (1.38 g, 13.61 mmol) and methanesulfonyl chloride (1.04 g, 9.07 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours. Upon completion, the reaction mixture was quenched with water (30 mL) at 0° C. and then extracted with dichloromethane (30 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]ethyl methanesulfonate (2.6 g, 3.64 mmol, 80%) as a yellow oil. m / z ES+ [M+H] + 629.4.

[0837] Intermediates 14, 23 and 15: tert-butyl (3S,4S)-4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate, 8-chloro-2-(1-((3S,4S)-3-fluoropiperidine 8-chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline and 8-chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline [ka] Step 1. (3S,4R)-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[0838] To a solution of (3S,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (500 mg, 2.28 mmol) in dichloromethane (5 mL) were added methanesulfonyl chloride (392 mg, 3.42 mmol) and triethylamine (692 mg, 6.84 mmol), and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,4R)-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (720 mg, crude product) as an orange solid. 1 H NMR(400MHz,DMSO-d6) δ 4.99-4.92(m,1H),4.91-4.83(m,1H),4.13-4.02(m,1H),3.88(s,1H),3.26( s,3H),3.24-3.07(m,1H),3.06-2.86(m,1H),1.91-1.77(m,2H),1.39(s,9H).

[0839] Step 2. (3S,4S)-tert-butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate

[0840] To a solution of 8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (600 mg, 1.18 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (491 mg, 3.55 mmol) and (3S,4R)-tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (704 mg, 2.37 mmol), and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was quenched with water (0.5 mL), concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (0.1% formic acid, 85-90% acetonitrile, 5 min) to afford (3S,4S)-tert-butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (600 mg, 849 μmol, 72%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 9.33(d,J=3.6Hz,1H),8.87(s,1H),8.44(s,1H),8-7.95(m,1H),7.70-7.57(m,1H),7.4 7-7.29(m,2H),7.10-6.99(m,1H),5.65-5.52(m,2H),5.01-4.80(m,1H),4.78-4.70(m,1 H),4.41-4.27(m,1H),4.10-3.96(m,1H),3.57-3.46(m,2H),3.10-2.93(m,2H),2.57(d ,J=6.8Hz,3H),2.17-2(m,2H),1.45(s,9H),0.87-0.77(m,2H),-0.06--0.15(m,9H);m / z ES+[M+H] + 708.3.

[0841] Step 3. 8-Chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

[0842] A solution of (3S,4S)-tert-butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (300 mg, 424 umol) in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was stirred at 25° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give 8-chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (250 mg, crude) as a yellow oil. 1 H NMR(400MHz,DMSO-d6) δ=9.52-9.45(m,1H),8.89(s,1H),8.53(s,1H),8.43(s,2H),8.10(d,J=9.2Hz,1H),7. 83-7.72(m,1H),7.60-7.42(m,2H),7.25-7.12(m,1H),5.81-5.61(m,2H),4.77-4.66(m ,1H),4.17(q,J=7.2Hz,1H),3.63(d,J=7.6Hz,3H),3.52-3.43(m,3H),3.17-3.05(m,2 H),2.71(d,J=6.4Hz,3H),2.37-2.25(m,3H),1.02-0.90(m,2H),0.09-0.01(m,9H);m / z ES+[M+H] + 608.3.

[0843] Step 4. 8-Chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

[0844] To a solution of 8-chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (250 mg, 411 umol) in tetrahydrofuran (2 mL) was added pyridine hydrofluoride (407 mg, 4.11 mmol) and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (0.1% formic acid, 30% to 40% acetonitrile, 5 min) to give 8-chloro-2-(1-((3S,4S)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-7-((2-methyl-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (120 mg, 251 μmol, 55%) as a white solid. m / z ES+ [M+H] + 478.2.

[0845] Intermediate 16: (2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)boronic acid [ka] Step 1. 6-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

[0846] To a solution of 5-bromo-2-methyl-1H-benzimidazole (20 g, 94.8 mmol) in THF (400 mL) was added NaH (7.58 g, 189 mmol, 60% in mineral oil) portionwise at 0° C. The reaction was stirred at 0° C. for 0.5 h. Then (2-(chloromethoxy)ethyl)trimethylsilane (23.7 g, 142 mmol, 25 mL) was added dropwise at 0° C. The mixture was stirred at 25° C. for 1.5 h. Upon completion, the reaction mixture was slowly poured into ice water (700 mL) and then extracted with ethyl acetate (300 mL×4). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (39 g, crude product, mixture of regioisomers) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ=7.87(s,0.5H),7.73(s,0.5H),7.58(d,J=8.4Hz,0.5H),7.48(d,J=8.4Hz,0.5H),7.36(dd,J=8.4,1.2Hz,0.5H),7.34( m / z ES+[M+H] + 341.1.

[0847] Step 2. 2-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

[0848] To a solution of 2-[(5-bromo-2-methyl-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (39.29 g, 115 mmol, mixture of regioisomers) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (87.69 g, 345 mmol) in dioxane (600 mL) was added potassium acetate (33.89 g, 345 mmol) and cyclopenta-2,4-dien-1-yl(diphenyl)phosphane; dichloropalladium; and iron(II) (8.42 g, 11.51 mmol). The mixture was stirred at 60° C. under nitrogen for 12 hours. Upon completion, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (44.2 g, 114 mmol, 99%, mixture of regioisomers) as a yellow solid. m / z ES+ [M+H] + 389.3.

[0849] Step 3. (2-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)boronic acid

[0850] To a solution of trimethyl-[2-[[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazol-1-yl]methoxy]ethyl]silane (25 g, 64.37 mmol) in tetrahydrofuran (250 mL) and water (250 mL) was added sodium periodate (41.30 g, 193 mmol) and ammonium acetate (14.89 g, 193 mmol). The mixture was stirred at 30° C. for 12 hours. Upon completion, the reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (300 mL×4). The combined organic layers were washed with saturated sodium sulfite (250 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (column: ID 100 mm × H 400 mm, mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile] (B%: 20-75%, 40 min; 75%, 35 min) to obtain (2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)boronic acid (8.2 g, 26.78 mmol, 42%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ=8.01(d,J=7.2Hz,1H),7.94(s,1H),7.92(s,1H),7.67-7.60(m,1H),7.52(d,J=8.4Hz,0.5H),7.48(d,J=8.4Hz,0.5H),5. 56(d,J=4.0Hz,2H),3.52(q,J=7.6Hz,2H),2.56(d,J=4.4Hz,3H),0.84(dd,J=14.0,8.0Hz,2H),-0.09(d,J=2.0Hz,9H);m / z ES+[M+H] + 307.2.

[0851] Intermediates 17, 20, and 30: 8-bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline, 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-ol, and 8-bromo-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline [ka] Step 1. 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-ol

[0852] To a solution of 7-bromo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline (4.90 g, 13.6 mmol) in dioxane (50 mL) and water (25 mL) was added tris(dibenzylideneacetone)dipalladium (1.25 g, 1.36 mmol), ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (579 mg, 1.36 mmol), and potassium hydroxide (7.65 g, 136 mmol). The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred under nitrogen at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10 / 1 to 1 / 1) to give 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-ol (1.70 g, 5.39 mmol, 39%) as a yellow solid. 1H NMR(400MHz,DMSO-d6) δ=10.44(s,1H),9.10(s,1H),8.78(s,1H),8.28(s,1H),7.87(d,J=8.8Hz,1H),7.29(dd,J=2.4,9.2Hz,1H),7.20(d,J=2.4Hz,1H),5.50(dd,J= 2.0,9.6Hz,1H),3.97(d,J=11.6Hz,1H),3.72-3.62(m,1H),2.22-2.10( m,1H),2.03-1.92(m,2H),1.77-1.64(m,1H),1.58(d,J=3.6Hz,2H);m / z ES+[M+H] + 297.1.

[0853] Step 2. 5-Bromo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-ol

[0854] To a solution of 3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-ol (1.70 g, 5.74 mmol) in chloroform (34 mL) was added N-bromosuccinimide (1.53 g, 8.61 mmol), dichloronickel (744 mg, 5.74 mmol), and triethylamine (581 mg, 5.74 mmol). The mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 25° C. and filtered. The filtrate was washed with saturated sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, filtered, and concentrated to give 5-bromo-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-ol (2.80 g, crude product) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=9.13(s,1H),8.79(s,1H),8.31(s,1H),7.87(d,J=9.2Hz,1H),7.46(d,J=9.2Hz,1H),5.54(dd,J=2.0,9.6Hz,1H) ,4.02-3.96(m,1H),3.74-3.61(m,1H),2.19-2.09(m,1H),2.04-1.93(m,2H),1.77-1.66(m,1H),1.61-1.54(m,2H).

[0855] Step 3. 8-Bromo-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline

[0856] To a solution of 5-bromo-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-ol (1.40 g, 3.73 mmol) and [2-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]boronic acid (1.22 g, 3.99 mmol) in 1,2-dimethoxyethane (30 mL) was added cesium carbonate (2.67 g, 8.21 mmol), 4Å MS (1.50 g), and copper(II) acetate (813 mg, 4.48 mmol). The mixture was stirred at 60° C. under an oxygen atmosphere for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1 to 1 / 5) to give 8-bromo-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (670 mg, 980 μmol, 26%) as a yellow solid. m / z ES+ [M+H] + 637.2.

[0857] Step 4. 8-Bromo-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline

[0858] To a solution of 2-[[6-[5-bromo-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (670 mg, 1.05 mmol) in methanol (7 mL) was added hydrochloric acid (1 M, 7 mL) and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 3 to 0 / 1) to give 8-bromo-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (360 mg, 587 μmol, 55%) as a yellow oil. m / z ES+ [M+H] + 553.1.

[0859] Step 5. 8-Bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

[0860] To a solution of 2-[[6-[5-bromo-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (290 mg, 526 μmol) and (3,3-difluorocyclobutyl)methyl methanesulfonate (158 mg, 789 μmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (218 mg, 1.58 mmol). The mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 8-bromo-2-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (430 mg, crude) as a yellow solid. m / z ES+ [M+H] + 657.2.

[0861] Intermediate 18: 8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline [ka] Step 1. 5-Chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-ol

[0862] To a solution of 3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-ol (4.50 g, 15.2 mmol) in chloroform (90 mL) was added 1-chloropyrrolidine-2,5-dione (4.06 g, 30.4 mmol), dichloronickel (1.97 g, 15.2 mmol), and diisopropylethylamine (2.94 g, 22.8 mmol). The mixture was stirred at 60 °C for 2 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 2-chloro-3-(2-fluoro-5-methoxyphenoxy)-6-nitroaniline (7 g, 21.2 mmol, 70% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=11.05(s,1H),9.19(s,1H),8.80(s,1H),8.32(s,1H),7.87(d,J=9.2Hz,1H),7.50(d,J=9.2Hz,1H),5.53(dd,J=2.0,9.6Hz,1 M / z ES+[M+H] + 331.0.

[0863] Step 2. 3-((5-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2-fluoro-6-nitroaniline

[0864] To a solution of 5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-ol (5.90 g, 17.8 mmol) and 2,3-difluoro-6-nitroaniline (3.11 g, 17.8 mmol) in N,N-dimethylformamide (160 mL) was added potassium carbonate (4.93 g, 35.7 mmol). The mixture was stirred at 130 °C for 4 hours. Upon completion, the reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). The resulting solid was triturated with petroleum ether / ethyl acetate (1 / 2, 30 mL) to give 3-chloro-4-(2-fluoro-5-methoxyphenoxy)benzene-1,2-diamine (6.59 g, 12.2 mmol, 69%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ=9.44(s,1H),8.90(s,1H),8.38(s,1H),8.09(d,J=9.2Hz,1H),7.86(dd,J= 1.6,9.6Hz,1H),7.69(d,J=9.2Hz,1H),7.48(s,2H),6.27(dd,J=7.6,9.6Hz,1 H),5.56(dd,J=2.0,9.6Hz,1H),3.99(d,J=11.6Hz,1H),3.74-3.66(m,1H),2. 21-2.10(m,1H),2.04-1.93(m,2H),1.78-1.67(m,1H),1.62-1.55(m,2H);m / z ES+[M+H] + 485.1.

[0865] Step 3. 4-((5-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-3-fluorobenzene-1,2-diamine

[0866] To a solution of 3-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-2-fluoro-6-nitro-aniline (6.59 g, 13.6 mmol) in ethanol (80 mL) and water (40 mL) was added ammonium chloride (7.27 g, 136 mmol) and iron powder (3.80 g, 68.0 mmol). The mixture was stirred at 60° C. for 12 hours. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (150 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 2) to give 4-((5-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-3-fluorobenzene-1,2-diamine (4.40 g, 9.38 mmol, 69%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=9.32(s,1H),8.86(s,1H),8.37(s,1H),7.94(d,J=9.2Hz,1H),7.23(d,J=9.2Hz,1H),6.42-6.31(m,2H),5.55(dd,J=2.4,9.6Hz,1H),4.84 (s,2H),4.72(s,2H),4.02-3.95(m,1H),3.74-3.66(m,1H),2.21-2.1 1(m,1H),2.06-1.97(m,2H),1.78-1.67(m,1H),1.62-1.55(m,2H);m / z ES+[M+H] + 455.1.

[0867] Step 4. 8-Chloro-7-((7-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline

[0868] To a solution of 4-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-3-fluoro-benzene-1,2-diamine (4.40 g, 9.67 mmol) and 1,1,1-trimethoxyethane (5.81 g, 48.4 mmol) in methanol (100 mL) was added sulfamic acid (1.88 g, 19.4 mmol). The mixture was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), then diluted with water (200 mL), and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 8-chloro-7-((7-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (4.80 g, crude) as a yellow solid. m / z ES+ [M+H] + 479.0.

[0869] Step 5. 8-Chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline

[0870] To a solution of 8-chloro-7-[(4-fluoro-2-methyl-3H-benzimidazol-5-yl)oxy]-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxaline (2.60 g, 5.43 mmol) in tetrahydrofuran (60 mL) was added sodium hydride (543 mg, 13.6 mmol, 60% in mineral oil) in portions at 0° C. The mixture was then stirred at 0° C. for 0.5 hours. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (1.36 g, 8.14 mmol) in anhydrous tetrahydrofuran (5 mL) was then added dropwise at 0° C. The mixture was stirred at 25° C. for 1 hour. Upon completion, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (2.90 g, 4.76 mmol, 88%) as a yellow solid. m / z ES+ [M+H] + 609.2.

[0871] Step 6. 8-Chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline

[0872] To a solution of 2-[[6-[5-chloro-3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (2.90 g, 4.76 mmol) in methanol (29 mL) was added aqueous hydrochloric acid (1 N, 29 mL). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was basified with saturated aqueous sodium bicarbonate to pH=8 and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (2.60 g, crude) as a white solid. m / z ES + [M+H] + 525.2.

[0873] Intermediate 19: 3-(4-(8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutan-1-one [ka] Step 1. 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline

[0874] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 952 μmol) and 2-bromo-5,8-dioxaspiro[3.4]octane (276 mg, 1.43 mmol) in N,N-dimethylformamide (8 mL) was added potassium carbonate (395 mg, 2.86 mmol) and potassium iodide (15.8 mg, 95.2 μmol). The mixture was stirred at 100° C. for 24 hours. Upon completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1 to 1 / 3) to give 2-(1-(5,8-dioxaspiro[3.4]octan-2-yl)-1H-pyrazol-4-yl)-8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxaline (460 mg, 686 μmol, 72%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ 9.32(d,J=2.8Hz,1H),8.82(s,1H),8.42(s,1H),7.95(dd,J=2.4,9.2Hz, 1H),7.56-7.44(m,1H),7.28-7.12(m,2H),5.63(d,J=10.4Hz,2H),4.89( t,J=8.0Hz,1H),3.96-3.84(m,4H),3.59-3.54(m,2H),2.95-2.79(m,4H) ,2.61(d,J=7.2Hz,3H),0.87-0.80(m,2H),0.07(s,4H),0.13(s,5H);m / z ES+[M+H] + 637.2.

[0875] Step 2. 3-(4-(8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanone

[0876] To a solution of 2-[[6-[5-chloro-3-[1-(5,8-dioxaspiro[3.4]octan-2-yl)pyrazol-4-yl]quinoxalin-6-yl]oxy-7-fluoro-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (360 mg, 565 μmol) in dichloromethane (1.8 mL) and water (0.5 mL) was added formic acid (4.39 g, 95.4 mmol, 3.6 mL). The mixture was stirred at 40 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and then adjusted to pH 8-9 with saturated aqueous sodium bicarbonate. The mixture was then extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1 to 1 / 3) to give 3-(4-(8-chloro-7-((7-fluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)cyclobutanone (280 mg, 467 μmol, 83%) as a yellow oil. m / z ES+ [M+H] + 593.2.

[0877] Intermediate 21: 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline [ka] Step 1. 2,4-Difluoro-6-nitro-3-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline

[0878] To a solution of 3-(1-tetrahydropyran-2-ylpyrazol-4-yl)quinoxalin-6-ol (3 g, 10.1 mmol) in 1-methylpiperidin-2-one (30 mL) was added cesium carbonate (6.60 g, 20.3 mmol) and 2,3,4-trifluoro-6-nitro-aniline (1.94 g, 10.1 mmol). The mixture was stirred at 110° C. for 2 hours. Upon completion, the reaction mixture was diluted with water (100 mL). The resulting precipitate was collected by filtration to give 2,4-difluoro-6-nitro-3-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (3.9 g, crude product) as a brown solid. 1 H NMR(400MHz,DMSO-d6) δ 9.30(s,1H),8.83(s,1H),8.28(s,1H),8.14-7.95(m,2H),7.69(dd,J=2.8,9.2Hz,1H),7.49(s,2H),7.39(d,J=2.8Hz,1H),5.49(dd,J=2. m / z ES+[M+H] + 469.2.

[0879] Step 2. 3,5-Difluoro-4-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzene-1,2-diamine

[0880] To a solution of 2,4-difluoro-6-nitro-3-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)aniline (3.9 g, 8.33 mmol) in ethanol (60 mL) and water (6 mL) was added iron powder (2.32 g, 41.6 mmol) and ammonium chloride (4.45 g, 83.3 mmol). The mixture was stirred at 60° C. for 2 hours. Upon completion, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 3,5-difluoro-4-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzene-1,2-diamine (5 g, crude) as a yellow solid. m / z ES+ [M+H] + 439.0.

[0881] Step 3. 7-((5,7-difluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline

[0882] To a solution of 3,5-difluoro-4-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)benzene-1,2-diamine (5 g, 11.4 mmol) in methanol (80 mL) was added 1,1,1-trimethoxyethane (6.85 g, 57.0 mmol) and sulfamic acid (2.21 g, 22.8 mmol). The mixture was stirred at 20° C. for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / methanol = 1 / 0 to 10 / 1) to give 7-((5,7-difluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (3.9 g, 6.75 mmol, 59%) as a yellow solid. 1H NMR(400MHz,CDCl3) δ 8.96(s,1H),8.43-7.93(m,3H),7.71-7.40(m,2H),7.11(s,1H),5.43(s,1H),4.06(d,J =10.4Hz,1H),3.86(s,3H),3.81-3.64(m,1H),2.17-1.97(m,3H),1.77-1.56(m,3H);m / z ES+[M+H] + 463.3.

[0883] Step 4. 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline

[0884] To a solution of 7-((5,7-difluoro-2-methyl-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (2.0 g, 4.32 mmol) in anhydrous tetrahydrofuran (60 mL) was added sodium hydride (1.04 g, 26.0 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 2 hours. Then (2-(chloromethoxy)ethyl)trimethylsilane (865 mg, 5.19 mmol) was added. The mixture was stirred at 20° C. for 14 hours. Upon completion, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 0 / 1) to give 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (600 mg, 810 μmol, 19%) as a yellow solid. m / z ES+ [M+18] + 593.4.

[0885] Step 5. 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline

[0886] To a solution of 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)quinoxaline (450 mg, 759 μmol) in methanol (5 mL) was added hydrochloric acid (1 M, 4.5 mL). The mixture was stirred at 20° C. for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to provide 7-((5,7-difluoro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)-2-(1H-pyrazol-4-yl)quinoxaline (600 mg, crude product) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 9.45-8.96(m,1H),8.61-8.51(m,1H),8.30(s,1H),8.18-7.99(m,1H),7.75-7.54(m,1H),7.27(s,1H),7.26-7. 13(m,1H),5.90-5.37(m,2H),3.76-3.49(m,2H),3.10-2.70(m,3H),1.06-0.78(m,2H),0.06--0.08(m,9H);m / z ES+[M+H] + 509.3.

[0887] Intermediate 22: 4,4-Difluorocyclohexyl methanesulfonate [ka] Step 1. 4,4-Difluorocyclohexyl methanesulfonate

[0888] To a solution of 4,4-difluorocyclohexanol (500 mg, 3.67 mmol) and triethylamine (743 mg, 7.35 mmol) in dichloromethane (1 mL) was added methanesulfonyl chloride (631 mg, 5.51 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 to 3:1) to give 4,4-difluorocyclohexyl methanesulfonate (750 mg, 3.50 mmol, 95%) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 4.95-4.92(m,1H),3.07(s,3H),2.13-1.87(m,8H).

[0889] Intermediate 23: 4-((4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclohexan-1-one [ka] Step 1. 1,4-Dioxaspiro[4.5]decan-8-yl methyl methanesulfonate

[0890] To a solution of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (500 mg, 2.90 mmol) and triethylamine (582 mg, 5.75 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (444 mg, 3.88 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (12 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1,4-dioxaspiro[4.5]decan-8-yl methyl methanesulfonate (850 mg, crude product) as a yellow oil. 1H NMR(400MHz,CDCl3) δ 4.05-3.95(m,2H),3.94-3.88(s,4H),2.99(s,3H),1.85-1.72(m,5H),1.54-1.51(m,1H),136-1.31(m,1H).

[0891] Step 2. 2-[[6-[5-chloro-3-[1-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0892] To a solution of 1,4-dioxaspiro[4.5]decan-8-ylmethyl methanesulfonate (370 mg, 1.48 mmol) and 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 986 mmol) in N,N-dimethylformamide (8 mL) was added potassium carbonate (300 mg, 2.17 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-[[6-[5-chloro-3-[1-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (900 mg, crude) as a yellow oil. m / z ES+ [M+H] + 661.3.

[0893] Step 3. 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclohexanone

[0894] To a solution of 2-[[6-[5-chloro-3-[1-(1,4-dioxaspiro[4.5]decan-8-ylmethyl)pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (900 mg, 1.36 mmol) in dichloromethane (4 mL) was added formic acid (4 mL). The mixture was stirred at 25 °C for 8 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water (2 mL) and adjusted to pH = 7 with saturated sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclohexanone (780 mg, crude) as a yellow oil. m / z ES+ [M+H] + 617.3.

[0895] Intermediate 24: 3-((4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-one [ka] Step 1. 2-[[6-[5-chloro-3-[1-[(3,3-dimethoxycyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane

[0896] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (150 mg, 296 μmol) and (3,3-dimethoxycyclobutyl)methyl methanesulfonate (79.6 mg, 355 μmol) in N,N-dimethylformamide (1.5 mL) was added potassium carbonate (123 mg, 887 μmol) and potassium iodide (49.1 mg, 296 μmol), and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic layers were washed with brine (3 x 3 mL), dried sodium sulfate, filtered, and concentrated in vacuo to give 2-[[6-[5-chloro-3-[1-[(3,3-dimethoxycyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (180 mg, crude) as a yellow oil. m / z ES+ [M+H] + 635.3.

[0897] Step 2. 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclobutanone

[0898] To a solution of 2-[[6-[5-chloro-3-[1-[(3,3-dimethoxycyclobutyl)methyl]pyrazol-4-yl]quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (180 mg, 283 μmol) in dichloromethane (1 mL) was added formic acid (13.6 mg, 283 μmol) and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was washed with saturated sodium bicarbonate solution (3 mL) and then extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-[[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]methyl]cyclobutanone (110 mg, crude) as a yellow gum. 1 H NMR(400MHz,DMSO-d6) δ 9.31(d,J=4.4Hz,1H),8.77(s,1H),8.38(s,1H),7.98-7.93(m,2H),7.70-7. 56(m,1H),7.48-7.26(m,2H),7.11-6.96(m,1H),5.75-5.30(m,2H),4.49(br d,J=6.4Hz,2H),3.58-3.45(m,2H),3.14(dt,J=6.4,11.8Hz,2H),3.01(br t,J=4.8Hz,2H),2.57(br d,J=6.4Hz,3H),0.93-0.71(m,2H),-0.05--0.17(m,9H);m / z ES+[M+H] + 589.3.

[0899] Intermediate 25: tert-butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-4-(2-hydroxyethyl)piperidine-1-carboxylate [ka] Step 1. tert-Butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0900] To a solution of 2-[[6-[5-chloro-3-(1H-pyrazol-4-yl)quinoxalin-6-yl]oxy-2-methyl-benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1 g, 1.97 mmol) in acetonitrile (10 mL) was added tert-butyl 4-(2-ethoxy-2-oxo-ethylidene)piperidine-1-carboxylate (595 mg, 2.21 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (330 mg, 2.17 mmol). The mixture was stirred at 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 1 / 0 to 80 / 1) to give tert-butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (900 mg, 1.04 mmol, 53%) as a yellow solid. m / z ES+ [M+H] + 776.5.

[0901] Step 2. tert-Butyl 4-(4-(8-chloro-7-((2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)oxy)quinoxalin-2-yl)-1H-pyrazol-1-yl)-4-(2-hydroxyethyl)piperidine-1-carboxylate

[0902] To a solution of tert-butyl 4-[4-[8-chloro-7-[2-methyl-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]oxy-quinoxalin-2-yl]pyrazol-1-yl]-...

Claims

[Claim 1] The invention described in this specification.

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